(aza)indole derivative and use thereof for medical purposes

ABSTRACT

The present invention provides compounds useful as agents for the prevention or treatment of a disease associated with abnormal serum uric acid level which has a uricosuric activity or the like. The present invention relates to (aza)indole derivatives represented by the following general formula (I) having xanthine oxidase inhibitory activities and useful as agents for the prevention or treatment of a disease associated with abnormality of serum uric acid level, prodrugs thereof, or salts thereof. In the formula (I), T represents nitro or cyano and the like; ring J represents aryl or heteroaryl and the like; Q represents carboxy or 5-tetazolyl and the like; Y represents H, OH, NH 2 , halogen, nitro, alkyl, alkoxy and the like; X 1 , X 2  and X 3  independently represent CR 2  or N; R 1  and R 2  independently represent halogen, cyano, haloalkyl, A-D-E-G, —N(-D-E-G) 2  and the like, in the formula, A represents a single bond, O, S and the like; D and G independently represent optionally substituted alkylene, cycloalkylene, heterocycloalkylene, arylene, heteroarylene and the like; E represents a single bond, O, S, COO, SO 2  and the like.

This application is a continuation of U.S. application Ser. No.13/116,389, filed on May 26, 2011, which is a divisional of U.S.application Ser. No. 12/595,476, filed on Oct. 9, 2009, now issued asU.S. Pat. No. 8,003,647, which is a National Stage of InternationalApplication No. PCT/JP2008/057089, filed on Apr. 10, 2008, which claimspriority to Japanese priority application No. 2007-104096 filed on Nov.4, 2007, which are all hereby incorporated by reference.

TECHNICAL FIELD

The present invention relates to (aza)indole derivatives useful asmedicaments.

More particularly, the present invention relates to (aza)indolederivatives having xanthine oxidase inhibitory activities and useful asagents for the prevention or treatment of a disease associated withabnormality of serum uric acid level, prodrugs thereof, orpharmaceutically acceptable salts thereof.

BACKGROUND ART

Uric acid is the final product of purine metabolism in human. In manymammals, unlike human, uric acid is further broken down by urate oxidase(uricase) in the liver into allantoin, which is excreted through thekidney. In human, main pathway of uric acid excretion is the kidney,wherein approximately two thirds of uric acid is excreted in urine. Theremaining is excreted in feces. When an excessive production ordecreased excretion of uric acid occurs, that causes hyperuricemia.Hyperuricemia is classified into a uric acid overproduction type, a uricacid underexcretion type and a mixed type thereof. This classificationof hyperuricemia is clinically important. Aiming for reducing adverseeffects of therapeutic agents, therapeutic agents are chosen accordingto each class (for example, see Non-patent reference 1).

In hyperuricemia with a uric acid overproduction type, urinary excretionof uric acid increases, and when the urinary excretion of uric acidfurther increases by using of a uricosuric drug, the complication ofurinary calculi is possibly developed. Therefore, in principle,allopurinol, a uric acid production inhibitor (or sometimes called auric acid synthesis inhibitor, hereinafter referred to as “a uric acidproduction inhibitor”), is used in a uric acid overproduction type.

Uric acid is produced from purine bodies, which are derived from dietand synthesized endogenously, finally by oxidizing xanthine by xanthineoxidase. Allopurinol is developed as a xanthine oxidase inhibitor and anonly uric acid production inhibitor used in medical practice. Whileallopurinol, however, is reported being effective in hyperuricemia andvarious diseases caused by the same, severe adverse effects such aspoisoning syndrome (hypersensitivity angiitis), Stevens-Johnsonsyndrome, exfoliative dermatitis, anaplastic anemia, liver dysfunctionand the like have been also reported (for example, see Non-patentreference 2). As one of the causes, it has been pointed out thatallopurinol has a nucleic acid-like structure and inhibits a pathway ofpyrimidine metabolism (for example, see Non-patent reference 3).

On the other hand, in hyperuricemia with a uric acid underexcretiontype, uric acid excretion decreases. It has been reported that whenallopurinol, which is metabolized into oxypurinol to be excreted throughthe kidney by the same mechanism to uric acid, is used, the excretion ofoxypurinol also decreases and that increases the incidence of liverdisorders (for example, see Non-patent reference 4). Therefore, inprinciple, uricosuric drugs such as probenecid, benzbromarone and thelike are used in a uric acid underexcretion type. These uricosuricdrugs, however, also exert adverse effects such as gastrointestinaldisorders, urinary calculi or the like. Particularly, benzbromarone isknown as possibly causing fluminant hepatitis in the case ofidiosyncratic patients (for example, see Non-patent reference 5).

Thus, it is said that both of the existing uric acid productioninhibitor and uricosuric drug have usage restrictions in patients orsevere adverse effects. Therefore, the development of an easy-to-useagent for the treatment of hyperuricemia has been desired.

Uric acid is eliminated mainly by the kidney, and the urate dynamics inthe kidney has been investigated so far in some experiments usingbrush-border membrane vesicles (BBMV) prepared from the renal cortex(for example, see Non-patent references 6 and 7). It has been known thatin human, uric acid is passed through the kidney glomerulus freely, andthere are mechanisms of reabsorption and secretion of uric acid in theproximal tubule (for example, see Non-patent reference 8).

In recent years, the gene (SLC22A12) encoding the human kidney uratetransporter has been identified (for example, see Non-patent reference9). The transporter encoded by this gene (urate transporter 1,hereinafter referred to as “URAT1”) is a 12-transmembrene type moleculebelonging to OAT family. URAT1 mRNA was specifically expressed in thekidney, and localization of URAT1 in apical side of the proximal tubulewas observed on the human kidney tissue section. In an experiment usingxenopus oocyte expression system, uptake of uric acid through URAT1 wasshown. Furthermore, it was shown that the uptake of uric acid istransported by exchange with organic anions such as lactic acid,pyrazinecarboxylic acid (PZA), nicotinic acid and the like, and the uricacid uptake through URAT1 is inhibited by uricosuric drugs, probenecidand benzbromarone. Thus, as expected by the experiment using membranevesicles, it was strongly suggested that URAT1 is a urate/anionexchanger. That is, it was shown that URAT1 is a transporter that playsan important role in uric acid reabsorption in the kidney (for example,see Non-patent reference 9).

In addition, the relation between URAT1 and diseases became clear.Idiopathic renal hypouricemia is a disease wherein uric acid excretionis increased due to abnormal urate dynamics in the kidney and the serumuric acid level becomes low. It is known that the disease is oftenassociated with urinary calculi or acute renal failure after exercise.URAT1 was identified as a causative gene of the renal hypouricemia (forexample, see Non-patent reference 9). These things also strongly suggestthat URAT1 is responsible for controlling the blood uric acid level.

Therefore, a substance having a URAT1 inhibitory activity is useful asan agent for the treatment and prevention of diseases associated withhigh blood uric acid levels, that is, hyperuricemia, gouty tophus, goutyarthritis, renal disorder associated with hyperuricemia, urinary calculior the like.

In the treatment of hyperuricemia, it was reported that a combination ofallopurinol of a uric acid production inhibitor and an agent having auricosuric activity lowered the serum uric acid level more strongly thanthe single use of allopurinol (for example, see Non-patent references 10and 11). Therefore, when treatment with a single existing agent can notexert effect enough, a higher therapeutic effect can be expected by acombination use of a uric acid production inhibitor and a uricosuricagent. Furthermore, for hyperuricemia with the uric acid underexcretiontype, it is considered that since urinary excretion of uric acid can bedecreased by lowering blood uric acid level, the risk of urinary calculicaused by the monotherapy with a uricosuric agent can be reduced. Inaddition, for hyperuricemia with the mixed type, high therapeutic effectis expected. Thus, an agent having both an inhibitory activity of uricacid production and a uricosuric activity is expected to become anextremely useful agent for the prevention or treatment of hyperuricemiaor the like.

As a compound having both xanthine oxidase inhibitory activity and URAT1inhibitory activity, morin, a natural product, is known (see Non-patentreference 12). In addition, as a compound having a uricosuric activity,biaryl or diaryl ether compounds are known (see Patent reference 1).

It was reported that 1-phenylindole derivatives have a stem celldifferentiation inhibitory effect (see Patent references 2 to 4). It wasalso reported that a 1-pyrimidine-indole derivative has a sodium channelinhibitory effect (see Patent reference 5). However, an (aza)indolederivative of the present invention has a different structure from thecompounds described in the above references, and anything is neitherdescribed nor suggested about that it has a xanthine oxidase inhibitoryactivity or is useful for the prevention or treatment of a diseaseassociated with abnormal serum uric acid level such as gout,hyperuricemia or the like.

-   Patent reference 1: Tokkai 2000-001431 (JPA2000-001431)-   Patent reference 2: The international publication 2005/007838    pamphlet-   Patent reference 3: Tokkai 2006-180763 (JPA2006-180763)-   Patent reference 4: Tokkai 2006-204292 (JPA2006-204292)-   Patent reference 5: The international publication 2005/003099    pamphlet-   Non-patent reference 1: Atsuo Taniguchi and 1 person, Modern    Physician, 2004, Vol. 24, No. 8, pp. 1309-1312-   Non-patent reference 2: Kazuhide Ogino and 2 persons, Nihon Rinsho    (Japan Clinical), 2003, Vol. 61, Extra edition 1, pp. 197-201-   Non-patent reference 3: Hideki Horiuchi and 6 persons, Life Science,    2000, Vol. 66, No. 21, pp. 2051-2070-   Non-patent reference 4: Hisashi Yamanaka and 2 persons,    Konyosankessyo to Tsufu (Hyperuricemia and gout), issued by Medical    Review Co., 1994, Vol. 2, No. 1, pp. 103-111-   Non-patent reference 5: edited by Konyosankessyo, tsufu no Chiryo    guideline sakuseiiinkai (The Committee establishing a guideline for    the treatment of hyperuricemia and gout), The guideline for the    treatment of hyperuricemia and gout, Edition 1, issued by Nihon    tsuhu kakusan taisya gakkai (Japanese society of gout and nucleic    acid metabolism), 2002, pp. 32-33-   Non-patent reference 6: Francoise Roch-Ramel and 2 persons, Am. J.    Physiol., 1994, Vol. 266 (Renal Fluid Electrolyte Physiol., Vol.    35), F797-F805-   Non-patent reference 7: Francoise Roch-Ramel and 2 persons, J.    Pharmacol. Exp. Ther., 1997, Vol. 280, pp. 839-845-   Non-patent reference 8: Hiroaki Kimura and 3 persons, Nihon rinsyo    (Japan Clinical), 2003, Vol. 61, Extra Edition 1, pp. 119-123-   Non-patent reference 9: Atsushi Enomoto and 18 persons, Nature,    2002, Vol. 417, pp. 447-452-   Non-patent reference 10: S Takahashi and 5 persons, Ann. Rheum.    Dis., 2003, Vol. 62, pp. 572-575-   Non-patent reference 11: M. D. Feher and 4 persons, Rheumatology,    2003, Vol. 42, pp. 321-325-   Non-patent reference 12: Zhifeng Yu and 2 persons, J. Pharmacol.    Exp. Ther., 2006, Vol. 316, pp. 169-175

DISCLOSURE OF THE INVENTION Problem that the Invention Aims to Solve

The present invention is to provide an agent which has an inhibitoryactivity of uric acid production for the prevention or treatment of adisease associated with abnormal serum uric acid level.

Means to Solve the Problem

The present inventors have earnestly to solve the above problem. As aresult, it was found that (aza)indole derivatives represented by thefollowing general formula (I) exert an excellent xanthine oxidaseinhibitory activity and extremely lower serum uric acid levels, andtherefore, they can be an agent for the prevention or treatment of adisease associated with abnormal serum uric acid level, thereby formingthe basis of the present invention.

That is, the present invention relates to:

[1] an (aza)indole derivative represented by the general formula:

-   wherein T represents nitro, cyano or trifluoromethyl;-   ring J represents an aryl ring or a heteroaryl ring;-   Q represents carboxy, lower alkoxycarbonyl, carbamoyl,    mono(di)(lower alkyl)carbamoyl, sulfo, sulfamoyl or 5-tetrazolyl;-   Y represents a hydrogen atom, hydroxyl, amino, a halogen atom,    nitro, optionally substituted lower alkyl or optionally substituted    lower alkoxy with the proviso that two or more Y optionally exist on    ring J and these Y are optionally the same or different from each    other;-   X¹, X² and X³ independently represent CR² or N with the proviso that    all of X¹, X² and-   X³ do not represent N at the same time, and when two or more R²    exist, these R² are optionally the same or different from each    other; and-   R¹ and R² independently represent a halogen atom, cyano,    perfluoro(lower alkyl), -A^(A), -A-D-E-G or —N(-D-E-G)₂ with the    proviso that two (-D-E-G) are optionally different from each other;-   in the formula, A^(A) represents a hydrogen atom, hydroxy, thiol,    —CHO, carboxy, —CONHR³, —NHR³, —N(R³)CHO, —N(R³)CONHR⁴ or —SO₂NHR³;-   A represents a single bond, —O—, —S—, —CO—, —COO—, —CON(R³)—, —SO₂—,    —SO₂N(R³)—, —N(R³)—, —N(R³)CO—, —N(R³)COO—, —N(R³)SO₂— or    —N(R³)CONR⁴— wherein R³ and R⁴ independently represent a hydrogen    atom or lower alkyl;-   D represents optionally substituted lower alkylene, optionally    substituted lower alkenylene, optionally substituted lower    alkynylene, optionally substituted cycloalkylene, optionally    substituted heterocycloalkylene, optionally substituted arylene or    optionally substituted heteroarylene with the proviso that D is    optionally further substituted by -E-G;-   E represents a single bond, —O—, —N(R⁵)—, —S—, —CO—, —COO—,    —CON(R⁵)—, —SO₂—, —SO₂N(R⁵)—, —N(R⁵)CO—, —N(R⁵)COO—, —N(R⁵)SO₂— or    —N(R⁵)CON(R⁶)— with the proviso that R⁵ and R⁶ independently    represent a hydrogen atom or lower alkyl; and-   G represents a hydrogen atom, optionally substituted lower alkyl,    optionally substituted lower alkenyl, optionally substituted lower    alkynyl, optionally substituted cycloalkyl, optionally substituted    heterocycloalkyl, optionally substituted aryl, optionally    substituted heteroaryl, optionally substituted cycloalkyl(lower    alkyl), optionally substituted heterocycloalkyl(lower alkyl),    optionally substituted aryl(lower alkyl) or optionally substituted    heteroaryl(lower alkyl) with the proviso that when G is a hydrogen    atom, E is a single bond, —O—, —N(R⁵)—, —S—, —COO—, —CON(R⁵)—,    —N(R⁵)CO—, —N(R⁵)CON(R⁶)— or —SO₂N(R⁵)—, or G optionally bind    together with R⁵ and R⁶ to form a ring, or with the proviso that    when R¹ and R² or two R² bound to the neighboring atoms exist, these    R¹ and R² or two R² optionally bind together to form a ring;    respectively, or a prodrug thereof, or a pharmaceutically acceptable    salt thereof;

[2] an (aza)indole derivative as described in the above [1], wherein X¹,X² and X³ independently represent CR² with the proviso that when two ormore R² exist; these R² are optionally the same or different from eachother, or a prodrug thereof, or a pharmaceutically acceptable saltthereof;

[3] an (aza)indole derivative as described in the above [1] or [2],wherein T represents cyano, or a prodrug thereof, or a pharmaceuticallyacceptable salt thereof;

[4] an (aza)indole derivative as described in any one of the above [1]to [3], wherein Q represents carboxy, or a prodrug thereof, or apharmaceutically acceptable salt thereof;

[5] an (aza)indole derivative as described in any one of the above [1]to [4], wherein Y represents a hydrogen atom, hydroxy or a halogen atom,or a prodrug thereof, or a pharmaceutically acceptable salt thereof;

[6] an (aza)indole derivative as described in the above [5], wherein Yrepresents hydroxy, or a prodrug thereof, or a pharmaceuticallyacceptable salt thereof;

[7] an (aza)indole derivative as described in any one of the above [1]to [6], wherein ring J represents a benzene ring, or a prodrug thereof,or a pharmaceutically acceptable salt thereof;

[8] an (aza)indole derivative as described in the above [4], wherein thegroup represented by the general formula:

is a group represented by the following general formula (IIa):

in the formula,

-   Z¹, Z² and Z³ independently represent CR⁷ or N; and-   Y¹ and R⁷ independently represent a hydrogen atom, hydroxy, amino, a    halogen atom, lower alkyl or lower alkoxy with the proviso that when    two or more R⁷ exist, these R⁷ are optionally the same or different    from each other, or a prodrug thereof, or a pharmaceutically    acceptable salt thereof;

[9] an (aza)indole derivative as described in the above [8], wherein Z¹and Z³ represent CH, and Z² represent CR⁸ or N; and

-   Y¹ and R⁸ independently represent a hydrogen atom, hydroxy or a    halogen atom, or a prodrug thereof, or a pharmaceutically acceptable    salt thereof;

[10] an (aza)indole derivative as described in any one of the above [4]to [6], wherein ring J represents a 5-membered heteroaryl ring having 1to 3 different or the same hetero atoms selected from the groupconsisting of an oxygen atom, a nitrogen atom and a sulfur atom in thering with the proviso that an oxygen atom and a sulfur atom do not existnext to each other; and Y represents a hydrogen atom, hydroxy, amino, ahalogen atom, optionally substituted lower alkyl or optionallysubstituted lower alkoxy with the proviso that two or more Y optionallyexits on ring J and these J are optionally the same or different fromeach other, or a prodrug thereof, or a pharmaceutically acceptable saltthereof;

[11] an (aza)indole derivative as described in the above [10], whereinthe group represented by the general formula:

is a group represented by the following general formula (IIb):

in the formula,

-   Z⁴, Z⁵ and Z⁷ represent an oxygen atom, a nitrogen atom, a sulfur    atom with the proviso that both of Z⁴ and Z⁵ are not atoms selected    from an oxygen atom and a sulfur atom at the same time, or CR⁹ in    which R⁹ represents a hydrogen atom, hydroxy, amino, a halogen atom,    lower alkyl or lower alkoxy with the proviso that when two or more    R⁹ exist, these R⁹ are optionally the same or different from each    other; Z⁶ represents a carbon atom; and Z⁴, Z⁵, Z⁶ and Z⁷ bind    together with the carbon atom bound by a carboxy group to form a    5-membered heteroaryl ring, or a prodrug thereof, or a    pharmaceutically acceptable salt thereof;

[12] an (aza)indole derivative as described in the above [4], whereinthe group represented by the general formula:

is a group represented by the following general formula (IId):

R¹ represents a hydrogen atom; X¹ represents CR¹⁰ wherein R¹⁰ representslower alkyl or —O-(lower alkyl)-; X² represents CR¹¹ wherein R¹¹represents a halogen atom or lower alkyl; and X³ represents CH; or aprodrug thereof, or a pharmaceutically acceptable salt thereof;

[13] an (aza)indole derivative as described in the above [12], whereinR¹⁰ represents methyl or methoxy; and R¹¹ represents a fluorine atom, achlorine atom or methyl; or a prodrug thereof, or a pharmaceuticallyacceptable salt thereof. an (aza)indole derivative as described in theabove [12], or a prodrug thereof, or a pharmaceutically acceptable saltthereof;

[14] a xanthine oxidase inhibitor comprising as an active ingredient an(aza)indole derivative as described in any one of the above [1] to [13],or a prodrug thereof, or a pharmaceutically acceptable salt thereof;

[15] a pharmaceutical composition comprising as an active ingredient an(aza)indole derivative as described in any one of the above [1] to [13],or a prodrug thereof, or a pharmaceutically acceptable salt thereof;

[16] a pharmaceutical composition as described in the above [15], whichis an agent for the prevention or treatment of a disease selected fromthe group consisting of hyperuricemia, gouty tophus, gouty arthritis,renal disorder associated with hyperuricemia and urinary calculi;

[17] a pharmaceutical composition as described in the above [16], whichis an agent for the prevention or treatment of hyperuricemia;

[18] a pharmaceutical composition as described in the above [15], whichis an agent for lowering serum uric acid level;

[19] a pharmaceutical composition as described in the above [15], whichis a uric acid production inhibitor;

[20] a pharmaceutical composition as described in any one of the above[15] to [19], which comprises a further combination with at least onedrug selected from the group consisting of colchicines, a non-steroidanti-inflammatory drug, a steroid and a urine alkalizer as an activeingredient; and the like.

In the (aza)indole derivatives represented by the above general formula(I) of the present invention, each term has the following meaning.

The term “halogen atom” means a fluorine atom, a chlorine atom, abromine atom or an iodine atom.

The term “lower” means a straight-chained or a branched hydrocarbongroup having 6 or less carbon atoms. For example, as lower alkyl,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, tent-pentyl, hexyl and thelike can be illustrated, as lower alkenyl, vinyl, allyl, 1-propenyl,isopropenyl, 1-butenyl, 2-butenyl, 2-methylallyl and the like can beillustrated, and as lower alkynyl, ethynyl, 2-propynyl and the like canbe illustrated. As lower alkylene, methylene, methylmethylene,dimethylmethylene, ethylene, 1-methylethylene, 2-methylethylene,propane-1,3-diyl, 1-methylpropane-1,3-diyl,1,1-dimethylpropane-1,3-diyl, 2-methylpropane-1,3-diyl,2,2-dimethylpropane-1,3-diyl, 3-methylpropane-1,3-diyl,3,3-dimethylpropane-1,3-diyl, butane-1,4-diyl, 1-methylbutane-1,4-diyl,1,1-dimethylbutane-1,4-diyl, 2,2-dimethylbutane-1,4-diyl,3,3-dimethylbutane-1,4-diyl, 4-methylbutane-1,4-diyl,4,4-dimethylbutane-1,4-diyl, pentane-1,5-diyl, 1-methylpentane-1,5-diyl,2-methylpentane-1,5-diyl, 3-methylpentane-1,5-diyl,4-methylpentane-1,5-diyl, 5-methylpentane-1,5-diyl, hexane-1,5-diyl andthe like can be illustrated, as lower alkenylene, vinylene,propene-1,3-diyl, 1-butene-1,4-diyl, 2-butene-1,4-diyl,1,3-butadiene-1,4-diyl, 1-pentene-1,5-diyl, 2-pentene-1,5-diyl,1,3-pentadiene-1,5-diyl, 1-hexene-1,6-diyl, 2-hexene-1,6-diyl,3-hexene-1,6-diyl, 1,3-hexadiene-1,6-diyl, 1,3,5-hexatriene-1,6-diyl andthe like can be illustrated, and as lower alkynylene, ethnylene,2-propynylene and the like can be illustrated. As lower alkoxy, methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy,pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, hexyloxy and thelike can be illustrated, and as lower alkoxycarbonyl, methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl,pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl,tert-pentyloxycarbonyl, hexyloxycarbonyl and the like can beillustrated.

The term “perfluoro(lower alkyl)” means the above lower alkyl which issubstituted by a fluorine atom, and methyl substituted by 1 to 3fluorine atoms or ethyl substituted by 1 to 5 fluorine atoms ispreferable.

The term “cycloalkyl” means cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl or cyclooctyl, and the term “cycloalkylene”means a divalent group derived from the above cycloalkyl.

The term “heterocycloalkyl” means a 3 to 8-membered aliphatic monocyclichydrocarbon group having any 1 or 2 hetero atoms selected from the groupconsisting of an oxygen atom, a sulfur atom and a nitrogen atom in thering and optionally having 1 or 2 oxo groups such as aziridino,azetidino, morpholino, 2-morpholinyl, thiomorpholino, 1-pyrrolidinyl,piperidino, 4-piperidinyl, 1-piperazinyl, 1-pyrrolyl, tetrahydrofuranyl,tetrahydropyranyl and the like, or a 5 to 6-membered aliphaticmonocyclic hydrocarbon group defined above which is fused with a benzenering, for example, 1,3-dioxoisoindolin-2-yl and the like, and the term“heterocycloalkylene” means a divalent group derived from the aboveheterocycloalkyl.

The term “aryl” means phenyl or naphthyl, and the term “arylene” means adivalent group derived from the above aryl.

The term “cycloalkyl(lower alkyl)” means the above lower alkylsubstituted by the above cycloalkyl, the term “heterocycloalkyl(loweralkyl)” means the above lower alkyl substituted by the aboveheterocycloalkyl, the term “aryl(lower alkyl)” means the above loweralkyl substituted by the above aryl, the term “heteroaryl(lower alkyl)”means the above lower alkyl substituted by the above heteroaryl. Asubstituent of optionally substituted cycloalkyl(lower alkyl) may be oneither cycloalkyl or lower alkyl. It is similar about optionallysubstituted heterocycloalkyl(lower alkyl), optionally substitutedaryl(lower alkyl), and optionally substituted heteroaryl(lower alkyl).

The term “heteroaryl” means a 5 or 6-membered aromatic heterocyclicgroup having any 1 to 4 hetero atoms selected from the group consistingof an oxygen atom, a sulfur atom and a nitrogen atom in the ring, whichis derived from thiazole, oxazole, isothiazole, isoxazole, pyridine,pyrimidine, pyrazine, pyridazine, pyrrole, furan, thiophene, imidazole,pyrazole, oxadiazole, thiadiazole, triazole, tetrazole, furazan or thelike, or a 5 or 6-membered aromatic heterocyclic group fused with a6-membered ring having any 1 to 4 hetero atoms selected from the groupconsisting of an oxygen atom, a sulfur atom and a nitrogen atom, whichis derived from indole, isoindole, benzofuran, isobenzofuran,benzothiophene, benzoxazole, benzothiazole, benzoisoxazole,benzoisothiazole, indazole, benzimidazole, quinoline, isoquinoline,phthalazine, quinoxaline, quinazoline, sinoline, indolizine,naphthyridine, pteridine or the like, and the term “heteroarylene” meansa divalent group derived from the above heteroaryl.

The term “optionally substituted” means which may have the same ordifferent 1 to 3 substituents.

As a substituent of optionally substituted lower alkyl, optionallysubstituted lower alkenyl, optionally substituted lower alkynyl,optionally substituted cycloalkyl or optionally substitutedheterocycloalkyl, for example, a fluorine atom, perfluoro (lower alkyl),—OW¹, —SW¹, carboxy, sulfo, lower alkyl, lower alkylsulfonyl, loweralkoxycarbonyl, —OCOW², —N(W²)COW³, —OCOOW⁴, —N(W²)COOW⁴,—NHC(═NH)—NW²W³, —NW²W³, —CONW²W³, —N(W⁵)CONW⁶W⁷, —N(W²)SO₂W⁵,—SO₂NW²W³, —SO₂W⁴; aryl which may have any 1 to 3 groups selected fromthe group consisting of a halogen atom, hydroxy, lower alkyl, loweralkoxy and trifluoromethyl; and heteroaryl which may have any 1 to 3groups selected from the group consisting of a halogen atom, hydroxy,lower alkyl, lower alkoxy and trifluoromethyl can be illustrated. As asubstituent of optionally substituted lower alkyl in Y, a fluorine atom,perfluoro(lower alkyl), lower alkyl, a hydroxyl group and lower alkoxycan be preferably illustrated.

As a substituent of optionally substituted lower alkoxy, a fluorineatom, perfluoro(lower alkyl), lower alkyl, hydroxyl group and loweralkoxy can be preferably illustrated.

As a substituent of optionally substituted aryl and optionallysubstituted heteroaryl, for example, a halogen atom, perfluoro(loweralkyl), cyano, nitro, —OW⁸, —SW⁸, carboxy, lower alkyl, loweralkylsulfonyl, lower alkoxycarbonyl, —OCOW², —N(W²)COW³, —OCOOW⁴,—N(W²)COOW⁴, —NHC(═NH)—W²W³, —NW²W³, —CONW²W³, —N(W⁵)CONW⁶W⁷,—N(W²)SO₂W⁵, —SO₂NW²W³, —SO₂W⁴; aryl which may have any 1 to 3 groupsselected from the group consisting of a halogen atom, hydroxy, loweralkyl, lower alkoxy and trifluoromethyl; and heteroaryl which may haveany 1 to 3 groups selected from the group consisting of a halogen atom,hydroxy, lower alkyl, lower alkoxy and trifluoromethyl, can beillustrated.

In the above, W¹ represents a hydrogen atom, lower alkyl,perfluoro(lower alkyl); aryl which may have any 1 to 3 groups selectedfrom the group consisting of a halogen atom, hydroxy, alkyl, loweralkoxy and trifluoromethyl; aryl(lower alkyl); or lower alkyl having 2to 6 carbon atoms which has a group selected from the group consistingof amino, mono(di)(lower alkyl)amino and lower alkylsulfonamide, withthe proviso that the oxygen or sulfur atom bound to W¹ and a nitrogenatom in W¹ bind to different carbon atoms;

-   W², W³, W⁵, W⁶ and W⁷ independently represent a hydrogen atom, lower    alkyl, aryl(lower alkyl), or W² and W³, and W⁵ and W⁶, or W⁶ and W⁷    may form an alicyclic amino with the binding nitrogen atom;-   W⁴ represents lower alkyl, or W² and W⁴ may form an alicyclic amino    with the binding nitrogen atom;    and W⁸ represents a hydrogen atom, lower alkyl, perfluoro(lower    alkyl); aryl which may have any 1 to 3 groups selected from the    group consisting of a halogen atom, hydroxy, alkyl, lower alkoxy and    trifluoromethyl; aryl(lower alkyl); or lower alkyl having 2 to 6    carbon atoms which has a group selected from the group consisting of    amino, mono(di)(lower alkyl)amino and lower alkylsulfonamide, with    the proviso that the oxygen or sulfur atom bound to W⁸ and a    nitrogen atom in W⁸ bind to different carbon atoms and when two —OW⁸    exist on neighboring carbon atoms in an aryl ring, these W⁸ may bind    together to form a methylene chain which may be substituted by 1 or    2 fluorine atoms or an ethylene chain which may be substituted by 1    to 4 fluorine atoms, respectively.

The term “mono(di)(lower alkyl)amino” means amino mono- ordi-substituted by the above lower alkyl, and the term “mono(di)(loweralkyl)carbamoyl” means carbamoyl mono- or di-substituted by the abovelower alkyl. The two lower alkyl groups in a di-substituted group may bedifferent from each other.

The term “alicyclic amino” means 3 to 8-membered cyclic amino optionallyhaving a hetero atom selected from the group consisting of an oxygenatom, a sulfur atom and a nitrogen atom other than a nitrogen atom atthe binding position in the ring, such as aziridino, azetidino,morpholino, thiomorpholino, 1-pyrrolidinyl, piperidino, 1-piperazinyl,1-pyrrolyl and the like, optionally having 1 or 2 oxo groups andoptionally having 1 or 2 double bonds in the ring, for example,2-oxo-1-pyrrolidinyl and the like.

A ring G and either of R⁵ and R⁶, or R¹ and R², or two R² optionallybind together to form represents optionally substituted cycloalkyl oroptionally substituted heterocycloalkyl, each of which may have 1 to 3oxo groups on the ring and 1 or 2 double bonds in the ring,respectively.

In the formula (I), as R¹, a halogen atom, cyano, a hydrogen atom,hydroxy, —O-(optionally substituted lower alkyl), optionally substitutedlower alkyl, optionally substituted aryl or the like is preferable, ahalogen atom, a hydrogen atom, hydroxy, lower alkoxy, lower alkyl or thelike is more preferable. In X¹ or X², as CR², a halogen atom, cyano,trifluoromethyl, a hydrogen atom, hydroxy, carboxy, mono(di)(loweralkyl)amino, optionally substituted lower alkyl, optionally substitutedlower alkenyl, cycloalkyl, cycloalkyl(lower alkoxy), optionallysubstituted aryl, optionally substituted heteroaryl, —O-(optionallysubstituted lower alkyl), —CO-(optionally substituted heterocycloalkyl),—CON(R³)-(optionally substituted lower alkyl), —N(R³)SO₂— (lower alkyl),—O-(lower alkylene)-N(R⁵)COO-(optionally substituted lower alkyl)wherein R³ and R⁵ have the same meanings as defined in the above [1] orthe like is preferable, a halogen atom, a hydrogen atom, hydroxy, loweralkyl, lower alkoxy or the like is more preferable; and in X³, a halogenatom, a hydrogen atom, lower alkyl or the like is preferable, and ahalogen atom or a hydrogen atom is more preferable.

In the (aza)indole derivatives represented by the general formula (I),in case that the group represented by the above formula (II) is a grouprepresented by the following formula (IIc) wherein Q^(C) representscarboxy or 5-tetrazoyl; X¹ and X² independently represent CR²; and amongR¹ and two R², any two of them represent a hydrogen atom, and the otherrepresents a hydrogen atom, lower alkyl, perfluoro(lower alkyl), ahalogen atom, cyano or lower alkoxy, as Y, hydroxy, amino, a halogenatom, nitro, optionally substituted lower alkyl or optionallysubstituted lower alkoxy is preferable with the proviso that two or moreY optionally exits on ring J and these Y are optionally different fromeach other, and hydroxy or amino is more preferable.

A preferable compound among the (aza)indole derivatives represented bythe above general formula (I) of the present invention also has a URAT1inhibitory activity. Accordingly, such a compound can exert anuricosuric effect in addition to an uric acid synthesis inhibitoryeffect, and show a superior lowering effect of serum uric acid level. Asa compound which also has a URAT1 inhibitory activity, for example, anindole derivative represented by the following general formula (IA) canbe illustrated.

In the formula, R¹ have the same meaning as defined above.

In other aspect, as a preferable compound which also has a URAT1inhibitory activity and exerts excellent pharmacokinetic, for example,an indole derivative represented by the following general formula (IB)can be illustrated.

In the formula, R^(2b) represents lower alkyl or lower alkoxy, andmethyl or methoxy is preferable. R^(2c) represents a halogen atom orlower alkyl, and a fluorine atom, a chlorine atom or methyl ispreferable.

The (aza)indole derivatives represented by the above general formula (I)of the present invention can be prepared, for example, by a methoddescribed below or a similar method thereto, or a method described inliteratures or a similar method thereto and the like. In addition, whena protective group is necessary, operations of introduction anddeprotection can be conducted optionally in combination according to ageneral method.

[Synthetic method 1]

In the formula, L represents a halogen atom and T, ring J, Q, Y, X¹ toX³ and R¹ have the same meanings as defined above.

Process 1

An (aza)indole derivative represented by the above general formula (1)of the present invention can be prepared by conducting a couplingreaction of Compound (2) and Compound (3) in an inert solvent or withoutany solvent in the presence of a base and optionally removing aprotective group. As the inert solvent, N,N-dimethylformamide,tetrahydrofuran, N-methylpyrolidone, 1,2-dimethoxyethane,dimethylsulfoxide, 1,2-diethoxyethane, 1,4-dioxane, a mixed solventthereof and the like can be illustrated. As the base, sodium hydride,potassium carbonate, cesium carbonate, sodium hydroxide, potassiumhydroxide, sodium methoxide and the like can be illustrated. Thereaction temperature is usually at room temperature to refluxtemperature, and the reaction time is usually from 30 minutes to 7 days,varying based on a used starting material, solvent and reactiontemperature or the like. In addition, in the present process, thereaction can be optionally conducted using a pressure-resistant reactioncontainer.

An (aza)indole derivative represented by the above general formula (1)of the present invention can be also prepared by conducting a couplingreaction of Compound (2) and Compound (3) in an inert solvent in thepresence of a base, a catalytic amount of copper iodide and a ligand andoptionally removing a protective group. As the inert solvent,N,N-dimethylformamide, tetrahydrofuran, N-methylpyrrolidinone,1,2-dimethoxyethane, dimethylsulfoxide, a mixed solvent thereof and thelike can be illustrated. As the base, potassium phosphate, potassiumcarbonate, cesium carbonate and the like can be illustrated. As theligand, N,N-dimethylethylenediamine,(1R,2R)-(−)-N,N′-dimethylcyclohexane-1,2-diamine,(1S,25)-(+)-N,N′-dimethylcyclohexane-1,2-diamine, proline,N,N-dimethylaminoglycine and the like can be illustrated. The reactiontemperature is usually at room temperature to reflux temperature, andthe reaction time is usually from 30 minutes to 7 days, varying based ona used starting material, solvent and reaction temperature or the like.In addition, in the present process, the reaction can be optionallyconducted by using a pressure-resistant reaction container.

The above reaction can be also conducted by a method described in thefollowing literature (a).

-   (a) Hui Zhang, Qian Cai, and Dawei Ma, J. Org. Chem., Vol. 70, No.    13, 2005, 5173.

In the formula, R^(a) represents a hydrogen atom or lower alkyl with theproviso that two R^(a) may be different and both R^(a) may bind togetherto form a ring, and T, ring J, Q, Y, X¹ to X³ and R¹ have the samemeanings as defined above.

Process 2

An (aza)indole derivative represented by the above general formula (1)of the present invention can be also prepared by conducting a couplingreaction of Compound (2) and Compound (4) in an inert solvent in thepresence of a base and a catalytic amount of copper acetate andoptionally removing a protective group. As the inert solvent,dichloromethane, 1,2-dichloroethane, N,N-dimethylformamide,tetrahydrofuran, N-methylpyrolidone, 1,2-dimethoxyethane, a mixedsolvent thereof and the like can be illustrated. As the base,triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine and thelike can be illustrated. The reaction temperature is usually at roomtemperature to reflux temperature, and the reaction time is usually from30 minutes to 7 days, varying based on a used starting material, solventand reaction temperature or the like. In addition, in the presentprocess, the reaction can be optionally conducted using apressure-resistant reaction container.

Among the (aza)indole derivatives represented by the above generalformula (I) of the present invention, Compound (1a) wherein Q representscarboxy can be also prepared, for example, by Synthetic method 2.

[Synthetic Method 2]

In the formula, T, ring J, Y, X¹ to X³ and R¹ have the same meanings asdefined above.

Process 3

An (aza)indole derivative (Ia) of the present invention can be alsoprepared by allowing Aldehyde compound (5) to react with an oxidant inan inert solvent in the presence or absence of a base. As the inertsolvent, dichloromethane, 1,4-dioxane, acetonitrile, acetone, hexane,cyclohexane, t-butanol, water, a mixed solvent thereof and the like canbe illustrated. As the base, sodium hydroxide, potassium hydroxide,lithium hydroxide and the like can be illustrated. As the oxidant,potassium permanganate, barium permanganate, silver oxide and the likecan be illustrated. The reaction temperature is usually at roomtemperature to reflux temperature, and the reaction time is usually from30 minutes to 7 days, varying based on a used starting material, solventand reaction temperature or the like. In addition, in the presentprocess, the reaction can be optionally conducted using apressure-resistant reaction container.

Among the (aza)indole derivatives represented by the above generalformula (I) of the present invention, Compound (1b) wherein T representscyano can be also prepared, for example, by Synthetic method 3.

[Synthetic Method 3]

In the formula, ring J, Q, Y, X¹ to X³ and R¹ have the same meanings asdefined above.

Process 4

Aldehyde compound (7) can be prepared by subjecting Compound (6) toformylation in an inert solvent in the presence of N,N-dimethylformamideand phosphoryl chloride. As the inert solvent, N,N-dimethylformamide,acetonitrile, benzene, toluene, chlorobenzene, dichloromethane,1,2-dichloroethane, chloroform, a mixed solvent thereof and the like canbe illustrated. The reaction temperature is usually at 0° C. to refluxtemperature, and the reaction time is usually from 30 minutes to 7 days,varying based on a used starting material, solvent and reactiontemperature or the like.

Process 5

An (aza)indole derivative (Ib) of the present invention can be alsoprepared by subjecting Aldehyde compound (7) to cyanation usinghydroxylamine or a hydrochloride salt thereof in an inert solvent in thepresence or absence of a base in the presence or absence of acondensation agent. As the inert solvent, N,N-dimethylformamide,acetonitrile, benzene, toluene, chlorobenzene, dichloromethane,1,2-dichloroethane, chloroform, N-methylpyrolidone a mixed solventthereof and the like can be illustrated. As the base, triethylamine,N,N-diisopropylethylamine, pyridine, 2,6-lutidine,1,8-diazabicyclo[5,4,0]-7-undecene, potassium carbonate, sodiumcarbonate and the like can be illustrated. As the condensation agent,acetic anhydride, thionyl chloride, phosphoric chloride,N,N′-dicyclohexylcarbodiimide, N,N′-carbonyl-diimidazole and the likecan be illustrated. The reaction temperature is usually at 0° C. toreflux temperature, and the reaction time is usually from 30 minutes to7 days, varying based on a used starting material, solvent and reactiontemperature or the like.

The above cyanation reaction may be also conducted by allowing Aldehydecompound (7) and hydroxylamine or a hydrochloride salt thereof to reactwith sodium formate in a formic acid solvent. The reaction temperatureis usually at 0° C. to reflux temperature, and the reaction time isusually from 30 minutes to 7 days, varying based on a used startingmaterial, solvent and reaction temperature or the like.

Among the (aza)indole derivatives represented by the above generalformula (I) of the present invention, Compound (Ic) wherein R¹ or R²represents A-D-E-G with the proviso that A represents —O—, —S— or—N(R³)—, or —N(-D-E-G)₂, with the proviso that D represents loweralkylene, and E, G and R³ have the same meanings as defined in the abovecan be also prepared, for example, by Synthetic method 4. In Syntheticmethod 4, as an example, it is described using an example wherein R¹represents —O-D^(A)-E-G in which D^(A) represents lower alkylene; X¹ toX³ represent CH.

[Synthetic Method 4]

In the formula, L² represents a halogen atom, methanesulfonyloxy,p-toluenesulfonyloxy or trifluoromethanesulfonyloxy, and D^(A), E, T,ring J, Q and Y have the same meanings as defined above.

Process 6-1

An (aza)indole derivative (Ic) of the present invention can be alsoprepared by alkylating Hydroxyindole compound (8) using Compound (9) inan inert solvent in the presence of a base and optionally in thepresence of a phase transfer catalyst. As the inert solvent, diethylether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane,N,N-dimethylformamide, dimethylsulfoxide, N-methylpyrolidone, benzene,toluene, dichloromethane, a mixed solvent thereof and the like can beillustrated. As the base, inorganic base of sodium carbonate, potassiumcarbonate, cesium carbonate, sodium hydride and the like, and organicbase of triethylamine, N,N-diisopropylethylamine, pyridine,2,6-lutidine, 1,8-diazabicyclo[5,4,0]-7-undecene and the like can beillustrated. As the phase transfer catalyst, tetra-n-butylammoniumchloride, tetra-n-butylammonium bromide, 18-crown-6 and the like can beillustrated. The reaction temperature is usually at room temperature toreflux temperature, and the reaction time is usually from 30 minutes to7 days, varying based on a used starting material, solvent and reactiontemperature or the like. In addition, in the present process, thereaction can be optionally conducted using a pressure-resistant reactioncontainer.

In the formula, D^(A), E, T, ring J, Q and Y have the same meanings asdefined above.

Process 6-2

An (aza)indole derivative (Ic) of the present invention can be alsoprepared by alkylating Compound (10) using Hydroxy compound (11) in aninert solvent in the presence of a condensation agent and a phosphorouscompound. As the inert solvent, diethyl ether, tetrahydrofuran,1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethyl-formamide,dimethylsulfoxide, N-methylpyrolidone, benzene, toluene,dichloromethane, a mixed solvent thereof and the like can beillustrated. As the condensation agent, ethyl azodicarboxylate,isopropyl azodicarboxylate, 1,1′-(azodicarbonyl)dipiperidine and thelike can be illustrated. As the phosphorous compound, triphenylphosphineand the like can be illustrated. The reaction temperature is usually atroom temperature to reflux temperature, and the reaction time is usuallyfrom 30 minutes to 7 days, varying based on a used starting material,solvent and reaction temperature or the like. In addition, in thepresent process, the reaction can be optionally conducted using apressure-resistant reaction container.

Among the (aza)indole derivatives represented by the above generalformula (I) of the present invention, Compound (1d) wherein R¹ or R²represents -A-D-E-G with the proviso that A represents a single bond andD represents optionally substituted alkenylene with the proviso that adouble bond exists next to A, optionally substituted arylene oroptionally substituted heteroarylene, and E and G have the same meaningsas defined above can be also prepared, for example, by Synthetic method5. In Synthetic method 5, as an example, it is described using anexample wherein R¹ represents -A^(B)-D^(B)-E-G wherein A^(B) representsa single bond, D^(B) represent optionally substituted alkenylene,optionally substituted arylene or optionally substituted heteroarylene;and X¹ to X³ represent CH.

[Synthetic Method 5]

In the formula, L⁴ represents a halogen atom ortrifluoromethanesulfonyl, D^(B) represents optionally substituted loweralkenylene, optionally substituted arylene or optionally substitutedheteroarylene, and E, T, ring J, Q and Y have the same meanings asdefined above.

Process 7 [Method 1]

An (aza)indole derivative (Id) of the present invention can be alsoprepared by conducting Suzuki-Miyaura coupling of Compound (12) usingthe corresponding arylboronic acid reagent or a heteroarylboronic acidreagent in an inert solvent in the presence of a base and a palladiumcatalyst. As the inert solvent, benzene, toluene, xylene, diethyl ether,tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dichloro-methane,1,2-dichloroethane, chloroform, methanol, ethanol, 2-propanol, butanol,N,N-dimethylformamide, N-methylpyrolidone, dimethylsulfoxide, water, amixed solvent thereof and the like can be illustrated. As the base,sodium carbonate, potassium carbonate, sodium hydroxide, potassiumhydroxide, sodium ethoxide, sodium methoxide, potassium fluoride, cesiumfluoride, triethylamine, N,N-diisopropylethylamine, pyridine,2,6-lutidine, 1,8-diazabicyclo[5,4,0]-7-undecene and the like can beillustrated. As the palladium catalyst, tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium,[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium and the likecan be illustrated. The reaction temperature is usually at 0° C. toreflux temperature, and the reaction time is usually from 30 minutes to7 days, varying based on a used starting material, solvent and reactiontemperature or the like. In addition, in the present process, thereaction can be optionally conducted using a pressure-resistant reactioncontainer.

Process 7 [Method 2]

An (aza)indole derivative (Id) of the present invention can be alsoprepared by conducting Mizorogi-Heck reaction of Compound (12) using thecorresponding alkene in an inert solvent in the presence of a base and apalladium catalyst. As the inert solvent, benzene, toluene, xylene,diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane,dichloromethane, 1,2-dichloroethane, chloroform, methanol, ethanol,2-propanol, butanol, N,N-dimethylformamide, N-methylpyrolidone,dimethylsulfoxide, water, a mixed solvent thereof and the like can beillustrated. As the base, triethylamine, N,N-diisopropylethylamine,pyridine, 2,6-lutidine, 1,8-diazabicyclo[5,4,0]-7-undecene and the likecan be illustrated. As the palladium catalyst, palladium acetate,palladium chloride, tetrakis(triphenylphosphine) palladium,dichlorobis(triphenylphosphine)palladium,[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium and the likecan be illustrated. In addition, the present reaction can be alsoconducted using a ligand depending on the kind of a palladium catalyst,and as the ligand, triphenylphosphine, tri-o-tolylphosphine,tri-t-butylphosphonium tetrafluoroborate and the like can beillustrated. The reaction temperature is usually at 0° C. to refluxtemperature, and the reaction time is usually from 30 minutes to 7 days,varying based on a used starting material, solvent and reactiontemperature or the like. In addition, in the present process, thereaction can be optionally conducted using a pressure-resistant reactioncontainer.

The arylation or hetero arylation reaction of Process 7 (Method 1) canbe also conducted, for example, by a method described in the followingliteratures (b) to (f).

-   (b) Anderson, K. W.; Buchwald, S. L. Angew Chem, Int Ed. 2005, 44    (38), 6173-6177.-   (c) Appukkuttan, P.; Van Der Eycken, E. et al. Synlett 2005, (1),    127-133.-   (d) Wang, W.; Xiong, C et al. Tetrahedron Lett. 2001, 42 (44),    7717-7719.-   (e) Yang, Y.; Martin, A. R. Synth Commun 1992, 22 (12), 1757-1762.-   (f) Billingsley, K. L.; Anderson, K. W.; Buchwald, S. L. Angew Chem,    Int Ed 2006, 45 (21), 3484-3488.

The alkenylation reaction of Process 7 (Method 2) can be also conducted,for example, by a method described in the following literatures (g) to(i).

-   (g) Hassner, A.; Loew, D. et al. J Org. Chem. 1984, 49 (14), 2546.-   (h) Leclerc, J.-P.; Andre, M. et al. J Org. Chem. 2006, 71 (4),    1711-1714.-   (i) Harrison, C.-A.; Jackson, P. M. et al. J Chem Soc, Perkin Trans    1, 1995, (9), 1131-1136.

Among the raw materials (2) used in the above processes, Compound (2a)wherein T represents cyano can be commercially available, or prepared bya known method or a similar method thereto and the like. In addition, itcan be prepared by the following method, a similar method thereto or thelike.

In the formula, L⁵ represents a halogen atom, X¹ to X³ and R¹ have thesame meanings as defined above.

Process 8

Amide compound (15) can be prepared by subjecting Carboxylic acidcompound (14) and ammonia to amidation optionally using an additive suchas 1-hydroxybenzotriazole or the like in an inert solvent in thepresence or absence of a condensing agent in the presence or absence ofa base. As the inert solvent, tetrahydrofuran, 1,4-dioxane,1,2-dimethoxyethane, benzene, toluene, xylene, dichloromethane,1,2-dichloroethane, chloroform, a mixed solvent thereof and the like canbe illustrated. As the condensing agent, acetic anhydride, thionylchloride, oxalyl chloride, N,N′-carbonyldiimidazole,N,N′-dicyclohexylcarbodiimide, diisopropyl-carbodiimide,N-ethyl-N′-3-dimethylaminopropylcarbodiimide and hydrochloride saltthereof, diphenylphosphorylazide and the like can be illustrated. As thebase, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine,1,8-diazabicyclo-[5,4,0]-7-undecene and the like can be illustrated. Thereaction temperature is usually at 0° C. to reflux temperature, and thereaction time is usually from 30 minutes to 7 days, varying based on aused starting material, solvent and reaction temperature or the like.

Process 9

Nitrile compound (2a) can be also prepared by dehydrating Amide compound(15) in an inert solvent in the presence of a dehydrating agent. As theinert solvent, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane,N,N-dimethylformamide, acetonitrile, benzene, toluene, xylene,dichloromethane, 1,2-dichloroethane, chloroform, a mixed solvent thereofand the like can be illustrated. As the dehydrating agent, aceticanhydride, thionyl chloride, phosphoryl chloride,methanesulfonylimidazole, p-toluenesulfonylchloride,N,N′-dicyclohexylcarbodiimide, diphosphorus pentoxide, triphosgene andthe like can be illustrated. The reaction temperature is usually at 0°C. to reflux temperature, and the reaction time is usually from 30minutes to 7 days, varying based on a used starting material, solventand reaction temperature or the like.

Process 10

Aldehyde compound (17) can be also prepared by subjecting. Compound (16)to formylation by a method similar to that as described in the aboveProcess 4.

Process 11

Nitrile compound (2a) can be also prepared by subjecting Aldehydecompound (17) to cyanation by a method similar to that as described inthe above Process 5.

Process 12

Halogeno compound (18) can be prepared by subjecting Compound (16) tohalogenation in an inert solvent in the presence of a halogenatingagent. As the inert solvent, tetrahydrofuran, 1,4-dioxane, acetic acid,dichloromethane, 1,2-dichloroethane, chloroform, a mixed solvent thereofand the like can be illustrated. As the halogenating agent, bromine,N-bromosuccinimide, pyridinium bromideperbromide, iodine and the likecan be illustrated. The reaction temperature is usually at 0° C. toreflux temperature, and the reaction time is usually from 30 minutes to7 days, varying based on a used starting material, solvent and reactiontemperature or the like.

Process 13

Nitrile compound (2a) can be also prepared by subjecting Halogenocompound (18) to cyanation in an inert solvent in the presence of acyanation reagent, a base and a palladium catalyst. As the inertsolvent, benzene, toluene, xylene, diethyl ether, tetrahydrofuran,1,4-dioxane, 1,2-dimethoxyethane, dichloromethane, 1,2-dichloroethane,chloroform, methanol, ethanol, 2-propanol, butanol,N,N-dimethylformamide, N-methylpyrolidone, dimethylsulfoxide, water, amixed solvent thereof and the like can be illustrated. As the cyanationreagent, sodium cyanide, potassium cyanide, copper cyanide, zinccyanide, trimethylsilyl cyanide and the like can be illustrated. As thebase, sodium carbonate, potassium carbonate, sodium hydroxide, potassiumhydroxide, sodium ethoxide, sodium methoxide, potassium fluoride, cesiumfluoride, triethylamine, N,N-diisopropylethylamine, pyridine,2,6-lutidine, 1,8-diazabicyclo[5,4,0]-7-undecene and the like can beillustrated. As the palladium catalyst, tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium,[1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium and the likecan be illustrated. The reaction temperature is usually at 0° C. toreflux temperature, and the reaction time is usually from 30 minutes to7 days, varying based on a used starting material, solvent and reactiontemperature or the like. In addition, in the present process, thereaction can be optionally conducted using a pressure-resistant reactioncontainer.

The cyanation reaction of Process 13 can be also conducted, for example,by a method described in the following literature (j), a similar methodthereto or the like.

-   (j) Sakamoto, T.; Ohsawa, K.; J Chem Soc, Perkin Trans 1 1999, (16),    2323-2326.

The raw materials (16) used in the above processes can be commerciallyavailable, or prepared, for example, by a method described in thefollowing literatures (k) to (n), a similar method thereto or the like.

-   (k) Rege, Pankaj D.; Tian, Yuan; Corey, E. J. Organic Letters, 2006,    8 (14), 3117-3120.-   (l) Wang, Jianji; Soundarajan, Nachimuthu; et al. Tetrahedron    Letters, 2005, 46 (6), 907-910.-   (m) Cacchi, Sandro; Fabrizi, Giancarlo; Parisi, Luca M. Organic    Letters, 2003, 5 (21), 3843-3846.-   (n) Bosco, Marcella; Dalpozzo, Renato; Bartoli, et al. Journal of    the Chemical Society, Perkin Transactions 2: Physical Organic    Chemistry, 1991, (5), 657-63.

In addition, it can be also prepared by a method shown in the followingSynthetic method 6, a similar method thereto or the like.

[Synthetic Method 6]

In the formula, X¹ to X³ and R¹ have the same meanings as defined above.

Process 14

Indole compound (16) can be also prepared by allowing Nitrobenzenederivative (19) or (20) to react using a metallic catalyst under anordinary pressure or a pressure under a hydrogen atmosphere in an inertsolvent. As the inert solvent, methanol, ethanol, n-butanol, aceticacid, ethyl acetate, tetrahydrofuran, N,N-dimethylformamide,acetonitrile, water, a mixed solvent thereof and the like can beillustrated. As the metallic catalyst, palladium carbon, rhodium carbon,platinum oxide(IV) and the like can be illustrated. The reactiontemperature is usually at 0° C. to reflux temperature, and the reactiontime is usually from 1 hour to 7 days, varying based on a used startingmaterial, solvent and reaction temperature or the like.

As the protective groups to be used in the present invention, variousprotective group generally used in organic reactions can be used. Forexample, as the protective groups of a hydroxyl group, in addition to ap-methoxybenzyl group, a benzyl group, a methoxymethyl group, an acetylgroup, a pivaloyl group, a benzoyl group, a tert-butyl-dimethylsilylgroup, a tert-butyldiphenylsilyl group, an allyl group and the like,when two hydroxyl groups are adjacent, an isopropylidene group, acyclopentylidene group, a cyclohexylidene group and the like can beillustrated. As the protective groups of a thiol group, ap-methoxybenzyl group, a benzyl group, an acetyl group, a pivaloylgroup, a benzoyl group, a benzyloxycarbonyl group and the like can beillustrated. As the protective groups of an amino group, abenzyloxycarbonyl group, a tert-butoxycarbonyl group, a benzyl group, ap-methoxybenzyl group, a trifluoroacetyl group, an acetyl group, aphthaloyl group and the like can be illustrated. As the protectivegroups of a carboxy group, a lower alkyl group, a benzyl group, atert-butyldimethylsilyl group, an allyl group and the like can beillustrated.

A compound represented by the above general formula (I) of the presentinvention can be isolated or purified by conventional isolationtechniques, such as fractional recrystallization, purification bychromatography, solvent extraction, solid-phase extraction and the like.

The (aza)indole derivatives represented by the above general formula (I)of the present invention can be converted into pharmaceuticallyacceptable salts thereof in the usual way. As such a salt, an acidadditive salt with a mineral acid such as hydrochloric acid, hydrobromicacid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid andthe like, an acid additive salt with an organic acid such as formicacid, acetic acid, methanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, propionic acid, citric acid, succinic acid,tartaric acid, fmaric acid, butyric acid, oxalic acid, malonic acid,maleic acid, lactic acid, malic acid, carbonic acid, benzoic acid,glutamic acid, aspartic acid and the like, an inorganic salt such as asodium salt, a potassium salt, a calcium salt, a magnesium salt, a zincsalt, a lithium salt, an aluminum salt and the like, a salt with anorganic amine such as N-methyl-D-glucamine,N,N′-dibenzylethylenediamine, 2-aminoethanol,tris(hydroxymethyl)aminomethane, arginine, lysine, piperadine, choline,diethylamine, 4-phenylcyclohexane and the like can be illustrated.

Of the (aza)indole derivatives represented by the above general formula(I) of the present invention, in a compound having an unsaturated bond,there are two geometrical isomers, a compound of cis (Z) form and acompound of trans (E) form. In the present invention, either of thecompounds can be employed, and a mixture thereof can be also employed.

Of the (aza)indole derivatives represented by the above general formula(I) of the present invention, in a compound having a chiral carbon atom,there are a compound of R form and a compound of S form for each chiralcarbon. In the present invention, either of the optical isomers can beemployed, and a mixture of the optical isomers thereof can be alsoemployed.

Of the (aza)indole derivatives represented by the above general formula(I) of the present invention, there can be some tautomers, the compoundsof the present invention also include these tautomers.

In the present invention, the term “prodrug” means a compound modifiedfrom a parent compound by a pharmaceutically acceptable group usuallyused in a prodrug, for example, which is given a property such asimprovement of stability, substantivity, oral absorbability or the like,and can be expected to be converted into the parent compound within anorganism (in the liver, the intestine and the like) to exert the effect.A prodrug of a compound represented by the above general formula (I) ofthe present invention can be prepared by introducing an appropriategroup forming a prodrug into any one or more groups selected from ahydroxy group, an amino group, a carboxy group and other groups whichcan form a prodrug of the compound represented by the above generalformula (I) using a corresponding reagent to produce a prodrug such as ahalide compound or the like in the usual way, and then by suitablyisolating and purificating in the usual way as occasion demands.Gekkan-Yakuji iyakuhin tekiseisiyou no tameno rinsyou yakubutudoutai(monthly pharmaceutical, clinical pharmacokinetics for the proper use ofpharmaceutical products), 2003.3. extra number Vol. 42, No. 4, p.669-707, New drug Drug delivery system Published by CMC Co., Ltd.,2000.1.31., p. 67-173. As a group forming a prodrug used in a hydroxygroup or an amino group, for example, (lower alkyl)-CO— such as acetyl,propionyl, butylyl, isobutylyl, pivaloyl and the like; aryl-CO— such asbenzoyl; (lower alkyl)-O-(lower alkylene)-CO—; (lower alkyl)-OCO-(loweralkylene)-CO—; (lower alkyl)-OCO— such as methyloxycarbonyl,ethyloxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl,tert-butyloxycarbonyl and the like; (lower alkyl)-O-(loweralkylene)-OCO—; (lower alkyl)-COO-(lower alkylene) such asacetyloxymethyl, pivaloyloxymethyl, 1-(acetyloxy)ethyl,1-(pivaloyloxy)ethyl and the like; (lower alkyl)-OCOO-(lower alkylene)such as methoxycarbonyloxymethyl, 1-(methoxycarbonyloxy)ethyl,ethoxycarbonyloxymethyl, 1-(ethoxycarbonyloxy)ethyl,isopropyloxycarbonyloxymethyl, 1-(isopropyloxycarbonyloxy)ethyl,tert-butyloxycarbonyloxymethyl, 1-(tert-butyloxycarbonyloxy)ethyl andthe like; cycloalkyl-OCOO-(lower alkylene) such ascyclohexyloxycarbonyloxymethyl, 1-(cyclohexyloxycarbonyl)ethyl and thelike; an ester or an amide with an amino acid such as glycine and thelike; and the like can be illustrated.

As a group forming a prodrug used in a carboxy group, for example, loweralkyl such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl andthe like; (lower alkyl)-COO-(lower alkylene) such as pivaloyloxymethyl,acetyloxymethyl, 1-(pivaloyloxy)ethyl, 1-(acetyloxy)ethyl and the like;(lower alkyl)-OCOO-(lower alkylene) such as ethyloxycarbonyloxymethyl,1-(ethyloxycarbonyloxy)ethyl, isopropyloxycarbonyloxymethyl,1-(isopropyloxycarbonyloxy)ethyl, tert-butyloxycarbonyloxymethyl,1-(tert-butyloxycarbonyloxy)ethyl and the like; cycloalkyl-OCOO-(loweralkylene) such as cyclohexyloxycarbonylmethyl,1-(cyclohexyloxycarbonyl)ethyl and the like; and the like can beillustrated.

An (aza)indole derivative represented by the general formula (I) or aprodrug thereof, or a pharmaceutically acceptable salt thereof can besometimes obtained as a hydrate or solvate thereof in the courses ofpurification or preparing salts thereof. An (aza)indole derivativerepresented by the general formula (I) of the present invention or aprodrug thereof, or a pharmaceutically acceptable salt thereof includesa hydrate thereof or a solvate thereof with a pharmaceuticallyacceptable solvent. As the pharmaceutically acceptable solvents, ethanoland the like can be illustrated.

A pharmaceutical composition of the present invention is useful as anagent for the prevention or treatment of diseases associated with highblood uric acid levels such as hyperuricemia, gouty tophus, goutyarthritis, renal disorder associated with hyperuricemia, urinary calculior the like, especially for hyperuricemia.

When a pharmaceutical composition of the present invention are employedin the practical prevention or treatment, the dosage of a compoundrepresented by the above general formula (I) or a prodrug thereof or apharmaceutically acceptable salt thereof as the active ingredient isappropriately decided depending on the age, sex, body weight and degreeof symptoms and treatment of each patient, for example, which isapproximately within the range of from 1 to 2,000 mg per day per adulthuman in the case of oral administration, and the daily dose can bedivided into one to several doses per day and administered.

When a pharmaceutical composition of the present invention are employedin the practical prevention or treatment, various dosage forms areorally or parenterally used depending on their uses, for example,formulations for oral administration such as powders, fine granules,granules, tablets, capsules, dry syrups or the like is preferable.

These pharmaceutical compositions can be prepared optionally by admixingusing an appropriate pharmaceutical additive such as excipients,disintegrators, binders, lubricants and the like, and formulating themixture in accordance with conventional methods.

For example, powders can be formulated by, if desired, admixing well anactive ingredient with appropriate excipients, lubricants and the like.For example, tablets can be formulated by tableting an active ingredientwith appropriate excipients, disintegrators, binders, lubricants and thelike in accordance with conventional methods, further if desired, can besuitably coated to provide film-coated tablets, sugar-coated tablets,enteric-coated tablets and the like. For example, capsules can beformulated by admixing well an active ingredient with appropriateexcipients, lubricants and the like, or formulating fine granules,granules in accordance with conventional methods, and filling it inappropriate capsules. Furthermore, in the case of such an oraladministration drug, it can be also formulated by conductingquick-release or sustained-release formulation depending on thepreventions or the treatment methods.

A compound represented by the above general formula (I) of the presentinvention, or a prodrug thereof or a pharmaceutically acceptable saltthereof can be used further in combination with any other drug for thetreatment of hyperuricemia or drug for the treatment of gout. As thedrug for the treatment of hyperuricemia which can be used in the presentinvention, for example, urinary alkalizers such as sodium hydrogencarbonate, potassium citrate and sodium citrate and the like can beillustrated. In addition, as the drug for the treatment of gout,colchicine, or non-steroidal anti-inflammatory drugs such asindomethacin, naproxen, fenbufen, pranoprofen, oxaprozin, ketoprofen,etoricoxib, tenoxicam and the like and steroids and the like can beillustrated. In the present invention, an active ingredient of thepresent invention can be also used further in combination with at leastone of these drugs, and a pharmaceutical composition comprisingcombination with at least one of these drugs includes any dosage formsof not only a single preparation comprising together with the activeingredient of the present invention but also a combination formulationconsisting of a pharmaceutical composition comprising the activeingredient of the present invention and a separately-preparedpharmaceutical composition for simultaneous administration oradministration at different dosage intervals. Furthermore, when used incombination with any drug other than the active ingredient of thepresent invention, the dosage of the compound of the present inventioncan be reduced depending on the dosage of the other drug used incombination, as the case may be, an advantageous effect more than anadditive effect in the prevention or treatment of the above diseases canbe obtained, or an adverse effect of the other drug used in combinationcan be avoided or declined.

Effect of the Invention

The (aza)indole derivatives represented by the above general formula (I)of the present invention exert an excellent xanthine oxidase inhibitoryactivity and suppress the production of uric acid. In addition, apreferable compound of the present invention can also exert an excellentURAT1 inhibitory activity and enhance the uric acid excretion.Therefore, the (aza)indole derivatives represented by the generalformula (I) of the present invention or a prodrugs thereof, orpharmaceutically acceptable salts thereof can extremely suppressincrease in serum uric acid level and are useful as an agent for theprevention or treatment of diseases associated with abnormal serum uricacid level such as hyperiuricemia or the like.

BEST MODE TO OPERATE THE INVENTION

The present invention is further illustrated in more detail by way ofthe following Reference Examples, Examples and Test Examples. However,the present invention is not limited thereto.

REFERENCE EXAMPLE 1 4-Fluoro-2-hydroxy-benzoic acid ethyl ester

To a solution of 4-fluoro-2-hydroxybenzoic acid (3.0 g) in ethanol (40mL) was added thionyl chloride (5.61 mL) at 0° C., and the mixture washeated under reflux for 24 hours. The reaction mixture was concentratedunder reduced pressure. This residue was poured into water, and theresulting mixture was extracted with ethyl acetate. The organic layerwas washed with water and brine, and dried over anhydrous magnesiumsulfate. The solvent was removed under reduced pressure to give thetitle compound (3.5 g).

REFERENCE EXAMPLE 2 4-Fluoro-2-methoxymethoxybenzoic acid ethyl ester

To a solution of 4-fluoro-2-hydroxybenzoic acid ethyl ester (3.5 g) indichloromethane (30 ml) were added N,N-diisopropylethylamine (5.0 g) and(chloromethyl)methyl ether (2.3 g) at 0° C., and this reaction mixturewas stirred at room temperature overnight. This reaction mixture waspoured into water, and the resulting mixture was extracted with ethylacetate. The organic layer was washed with water and brine, and driedover anhydrous magnesium sulfate. The solvent was removed under reducedpressure. The residue was purified by column chromatography on silicagel (eluent: n-hexane/ethyl acetate) to give the title compound (2.8 g).

REFERENCE EXAMPLE 3 4-Fluoro-2-methoxymethoxybenzoic acid methyl ester

To a solution of 4-fluoro-2-hydroxybenzoic acid (3.0 g) inN,N-dimethylformamide (5 mL) were added sodium hydride (60% 1.0 g) and(chloromethyl)methyl ether (2.1 g) at room temperature, and this mixturewas stirred for 48 hours at the same temperature. This reaction mixturewas poured into 2 mol/L hydrochloric acid and the resulting mixture wasextracted with ethyl acetate. The organic layer was washed with brine,and dried over anhydrous magnesium sulfate. The solvent was removedunder reduced pressure. The residue was purified by columnchromatography on silica gel (eluent: n-hexane/ethyl acetate) to givethe title compound (0.22 g).

REFERENCE EXAMPLE 4 5,6-Difluoro-1H-indole-3-carbaldehyde

To a solution of 5,6-difluoro-1H-indole (1.0 g) in N,N-dimethylformamide(10 mL) was added phosphoryl chloride (1.2 g) at 0° C., and this mixturewas stirred at room temperature for 4 hours. To this mixture was added 2mol/L aqueous sodium hydroxide solution (5 mL), and this resultingmixture was stirred at 70° C. for 0.5 hours. After cooling to ambienttemperature, this mixture was poured into 1 mol/L hydrochloric acid andthe resulting mixture was extracted with ethyl acetate. The organiclayer was washed with water and brine, and dried over anhydrousmagnesium sulfate. The solvent was removed under reduced pressure togive the title compound (1.1 g).

REFERENCE EXAMPLE 5 5,6-Difluoro-1H-indole-3-carbonitrile

To a solution of 5,6-difluoro-1H-indole-3-carbaldehyde (1.0 g) intetrahydrofuran (15 ml) were added hydroxylamine hydrochloride (0.81 g)and pyridine (1.9 g), and this mixture was stirred at 80° C. for 8hours. Acetic anhydride was added to reaction mixture and this mixturewas stirred at 80° C. for 8 hours. After cooling to ambient temperature,2 mol/L aqueous sodium hydroxide solution was added to this mixture andresulting mixture was stirred for 30 minutes. This mixture was pouredinto 2 mol/L hydrochloric acid and the precipitated solid was collectedby filtration, and washed with water and n-hexane. The solid wasdissolved in ethyl acetate and this residue was purified by columnchromatography on silica gel (eluent: n-hexane/ethyl acetate) to givethe title compound (0.95 g).

REFERENCE EXAMPLE 6 6-Fluoro-1H-indole-3-carbonitrile

To a solution of 6-fluoro-1H-indole-3-carbaldehyde (0.97 g) in 90%formic acid (25 mL) were added hydroxylamine (0.65 g) and sodium formate(0.81 g), and this mixture was stirred at 100° C. for 3 hours. Aftercooling to ambient temperature, water was added to this reaction mixtureand the precipitated solid was collected by filtration, and washed withwater, dried to give the title compound (0.57 g).

REFERENCE EXAMPLE 7 5-Phenyl-1H-indole-carbonitrile

The title compound was prepared in a similar manner to that described inReference Example 5 using the corresponding starting materials.

REFERENCE EXAMPLE 8 3-Formyl-1H-indole-5-carboxylic acid benzyl ester

To a solution of 1H-indole-5-carboxylic acid benzyl ester (3.5 g) inN,N-dimethylformamide (30 mL) was added phosphoryl chloride (2.6 g)under ice cooling and this mixture was stirred at room temperature for 2hours. To this reaction mixture was added 2 mol/L aqueous sodiumhydroxide solution until the pH became 6 and this mixture was stirred at70° C. for 30 minutes. After cooling to ambient temperature, theprecipitated solid was collected by filtration, and washed with waterand methanol, dried to give the title compound (3.9 g).

Reference compound 9

3-Cyano-1H-indole-5-carboxylic acid benzyl ester

To a solution of 3-formyl-1H-indole-5-carboxylic acid benzyl ester (4.3g) and pyridine (4.8 g) in tetrahydrofuran (60 ml) was addedhydroxylamine hydrochloride (1.6 g) at room temperature and this mixturewas stirred at 80° C. overnight. Acetic anhydride was added to reactionmixture at the same temperature and this mixture was stirred for 8hours. After cooling to ambient temperature, 1 mol/L sodium hydroxidesolution (20 mL) was added to this mixture and resulting mixture wasextracted with diethyl ether. The organic layer was washed with brine,and dried over anhydrous magnesium sulfate. The solvent was removedunder reduced pressure and this residue was purified by columnchromatography on silica gel (eluent: n-hexane/ethyl acetate) to givethe title compound (2.8 g).

REFERENCE EXAMPLE 10 3-Benzyloxy-4-methylbenzoic acid benzyl ester

To a solution of 3-hydroxy-4-methylbenzoic acid (5.0 g) inN,N-dimethylformamide (100 mL) were added cesium carbonate (32 g) andbenzyl bromide (12 g) at the same temperature and this mixture wasstirred at room temperature for 2 days. To this reaction mixture wasadded a saturated aqueous sodium bicarbonate solution and this mixturewas extracted with ethyl acetate. The organic layer was washed withbrine, and dried over anhydrous magnesium sulfate. The solvent wasremoved under reduced pressure and this residue was purified by columnchromatography on silica gel (eluent: n-hexane/ethyl acetate) to givethe title compound (7.5 g).

REFERENCE EXAMPLE 11 (3-Benzyloxy-4-methylphenyl)methanol

To a suspension of lithium aluminum hydride in diethyl ether (50 mL) wasadded dropwise a solution of 3-Benzyloxy-4-methyl-benzoic acid benzylester (7.5 g) in diethyl ether (11 mL) under argon atmosphere at 0° C.,and this mixture was stirred at room temperature for 6 hours. To thisreaction mixture was added dropwise water (3.2 mL), and then Celite wasadded to this mixture and filtered. This filtrate was concentrated togive title compounds as a mixture of benzyl alcohol (7.0 g).

REFERENCE EXAMPLE 12 3-Benzyloxy-4-methylbenzaldehyde

To a solution of (3-benzyloxy-4-methylphenyl)methanol (1.0 g) indichloromethane (50 mL) was added manganese dioxide (2.5 g), and thismixture was stirred at room temperature for 2 days. The insolublematerial was removed by filtration and this filtrate was concentratedunder reduced pressure. This residue was purified by columnchromatography on silica gel (eluent: n-hexane/ethyl acetate) to givethe title compound (0.39 g)

REFERENCE EXAMPLE 13 5-Benzyloxy-2-bromo-4-methylbenzaldehyde

To a solution of 3-benzyloxy-4-methylbenzaldehyde (0.39 g) in a mixedsolvent of dichloromethane (1 mL) and methanol (1 mL) was added asolution of bromine (0.410 g) in dichloromethane (0.2 mL) at 0° C. andthis mixture was stirred at room temperature for 2 hours. This mixturewas poured into water and the resulting mixture was extracted withdichloromethane. The organic layer was washed with brine, and dried overanhydrous magnesium sulfate. The solvent was removed under reducedpressure. The residue was purified by column chromatography on silicagel (eluent: n-hexane/ethyl acetate) to give the title compound (0.39g).

REFERENCE EXAMPLE 14(Z)-3-(5-Benzyloxy-2-bromo-4-methylphenyl)-2-benzyloxycarbonylaminoacrylicacid methyl ester

To a solution of 5-benzyloxy-2-bromo-4-methylbenzaldehyde (0.39 g) andN-(benzyloxycarbonyl)-alpha-phosphonoglycine trimethyl ester (0.38 g) indichloromethane (2 mL) was added 1,1,3,3-tetramethylguanidine (0.18 g)at room temperature and this mixture was stirred at room temperature for2 days. To this reaction mixture was added 1 mol/L hydrochloric acid andthe precipitated solid was collected by filtration, and washed withwater, dried under reduced pressure to give the title compound (0.34 g).

REFERENCE EXAMPLE 15 5-Benzyloxy-6-methyl-1H-indole-2-carboxylic acidmethyl ester

To a solution of(Z)-3-(5-benzyloxy-2-bromo-4-methylphenyl)-2-benzyloxy-carbonylaminoacrylicacid methyl ester (0.2 g) and copper (I) iodide (0.075 g) indimethylsulfoxide (8 mL) was added cesium acetate (0.38 g) at roomtemperature and this mixture was stirred under argon atmosphere at 90°C. for 5 hours. To this reaction mixture was added aqueous ammoniasolution (28%) and the precipitated solid was collected by filtration,and washed with water, dried under reduced pressure to give the titlecompound (0.073 g).

REFERENCE EXAMPLE 16 5-Benzyloxy-6-methyl-1H-indole-2-carboxylic acid

To a solution of 5-benzyloxy-6-methyl-1H-indole-2-carboxylic acid methylester (1.3 g) in a mixed solvent of 1,4-dioxane (40 mL) and water (20mL) was added Lithium hydroxide mono hydrate (1.8 g) at room temperatureand this mixture was stirred at 50° C. for 1 hour. After this reactionmixture was cooled to room temperature, 1 mol/L hydrochloric acid wasadded. This precipitated solid was collected by filtration, and washedwith water, dried under reduced pressure to give the title compound (1.0g).

REFERENCE EXAMPLE 17 5-Benzyloxy-6-methyl-1H-indole

To a solution of 5-benzyloxy-6-methyl-1H-indole-2-carboxylic acid (0.6g) in quinoline (6 mL) was added copper powder (0.15 g), and thismixture was stirred at 220° C. for 20 minutes. This reaction mixture waspoured into 1 mol/L hydrochloric acid, the resulting mixture wasextracted with ethyl acetate. This organic layer was washed with brine,and dried over anhydrous magnesium sulfate. The solvent was removedunder reduced pressure. The residue was purified by columnchromatography on silica gel (eluent: n-hexane/ethyl acetate) to givethe title compound (0.21 g).

REFERENCE EXAMPLE 18 5-Benzyloxy-6-methyl-1H-indole-3-carbaldehyde

The title compound (0.48 g) was prepared in a similar manner to thatdescribed in Reference Example 4 using the corresponding startingmaterials.

REFERENCE EXAMPLE 19 5-Benzyloxy-6-methyl-1H-indole-3-carbonitrile

The title compound (0.10 g) was prepared in a similar manner to thatdescribed in Reference Example 5 using the corresponding startingmaterials.

REFERENCE EXAMPLE 20 4-(6-Nitroindol-1-yl) benzoic acid ethyl ester

To a solution of 6-nitro-1H-indole (0.5 g) in N,N-dimethylformamide (10mL) were added cesium carbonate (1.2 g) and 4-fluoro benzoic acid ethylester (0.62 g), and this mixture was stirred at 75° C. overnight. Thisreaction mixture was poured into water and the precipitated solid wascollected by filtration, and washed with water and n-hexane, dried underreduced pressure to give the title compound (0.64 g).

REFERENCE EXAMPLE 21 1-(5-Formylfuran-2-yl)-1H-indole-3-carbonitrile

A suspension of 3-cyanoindole (0.14 g), 5-bromo-2-furaldehyde (0.18 g),and cesium carbonate (0.39 g) in N,N-dimethylformamide (3 mL) wasstirred at room temperature or 3 hours. This reaction mixture was heatedat 50° C., stirred for 2 hours. After cooling to ambient, water wasadded to this reaction mixture. This mixture was extracted with ethylacetate, and this organic layer was washed with brine, and dried overanhydrous magnesium sulfate. The solvent was removed under reducedpressure. The residue was purified by column chromatography on silicagel (eluent: n-hexane/ethyl acetate=2/1) to give the title compound(0.086 g).

REFERENCE EXAMPLE 22 4-(6-Formylindol-1-yl)benzoic acid ethyl ester

The title compound was prepared in a similar manner to that described inReference Example 20 using the corresponding starting materials.

REFERENCE EXAMPLE 23 4-(6-Acetoxymethyl-indol-1-yl)benzoic acid ethylester

To a solution of 4-(6-formylindol-1-yl)benzoic acid ethyl ester in amixed solvent of tetrahydrofuran (3 mL) and methanol (10 mL) was addedsodium borohydride (0.075 g) at 0° C., and this mixture was stirred atroom temperature for 0.5 hours. This reaction mixture was poured into asaturated aqueous ammonium chloride solution and this mixture wasextracted with ethyl acetate. This organic layer was washed with brine,and dried over anhydrous magnesium sulfate. The solvent was removedunder reduced pressure to give 4-(6-hydroxymethyl-indol-1-yl)benzoicacid ethyl ester (0.38 g). To a solution of4-(6-hydroxymethyl-indol-1-yl)benzoic acid ethyl ester (0.09 g) indichloromethane (1 mL) were added acetic anhydride (0.093 g) andpyridine (0.024 g), and this mixture was stirred at room temperature for2 days. This mixture was poured into water and the resulting mixture wasextracted with ethyl acetate. This organic layer was washed with brine,and dried over anhydrous magnesium sulfate. The solvent was removedunder reduced pressure. The residue was purified by columnchromatography on silica gel (eluent: n-hexane/ethyl acetate) to givethe title compound (0.068 g).

REFERENCE EXAMPLE 24 Methyl 4-fluoro-2-methyl carbonate

To a solution of 4-fluoro-2-methylphenol (2.0 g) in 1,4-dioxane (20 mL)were added methyl chloroformate (3.0 g) and pyridine (2.5 g) at underice cooling and this mixture was stirred at room temperature overnight.The insoluble material was removed by filtration and 1 mol/Lhydrochloric acid was added to this filtrate. This mixture was extractedwith ethyl acetate and the organic layer was washed with water twice,and dried over anhydrous magnesium sulfate. The solvent was removedunder reduced pressure to give the title compound.

REFERENCE EXAMPLE 25 4-Fluoro-2-methyl-5-nitrophenol

To a solution of methyl 4-fluoro-2-methyl carbonate (2.9 g) inconcentrated sulfuric acid (11 mL) was added fuming nitric acid (1.1 mL)in a dropwise manner over 10 min under ice cooling, and this mixture wasstirred at the same temperature for 1 hour. This reaction mixture waspoured into ice water and this mixture was extracted with ethyl acetate.This organic layer was washed with water twice, and dried over anhydrousmagnesium sulfate. The solvent was removed under reduced pressure. Thisresidue was dissolved in methanol, to this solution was added sodiumbicarbonate (2.6 g) and potassium carbonate (2.2 g) at room temperatureand this mixture was stirred for 2 hours. To the reaction mixture wasadded 1 mol/L hydrochloric acid until the pH became 1 and this organicsolvent was removed under reduced pressure. This residue was extractedwith ethyl acetate and the organic layer was washed with water andbrine, dried over anhydrous magnesium sulfate. The solvent was removedunder reduced pressure. The residue was purified by columnchromatography on silica gel (eluent: n-hexane/ethyl acetate) to givethe title compound (1.5 g).

REFERENCE EXAMPLE 26 1-Fluoro-4-methoxy-5-methyl-2-nitrobenzene

To a solution of 4-fluoro-2-methyl-5-nitrophenol (0.5 g) inN,N-dimethylformamide (5 mL) were added potassium carbonate (0.44 g) andiodomethane (0.46 g), and this mixture was stirred at room temperatureovernight. To this reaction mixture was added water and the precipitatedsolid was collected by filtration, and washed with water and n-hexane togive the title compound (0.44 g).

REFERENCE EXAMPLE 27 Cyano-(4-methoxy-5-methyl-2-nitrophenyl)acetic acidmethyl ester

To a suspension of sodium hydride (0.86 g) in N,N-dimethylformamide (5mL) was added dropwise a solution of cyano acetic acid methyl ester(0.35 g) in N,N-dimethylformamide (3 mL) under ice cooling and thismixture was stirred for 15 minutes. To this reaction mixture was addeddropwise a solution of 1-fluoro-4-methoxy-5-methyl-2-nitrobenzene (0.44g) under ice cooling and this mixture was stirred at room temperaturefor 30 minutes, and then stirred at 70° C. overnight. After cooling toambient temperature, 1 mol/L hydrochloric acid (5 mL) was added to thisreaction mixture. This resulting mixture was extracted with ethylacetate. This organic layer was washed with water and brine, and driedover anhydrous magnesium sulfate. The solvent was removed under reducedpressure. The residue was purified by column chromatography on silicagel (eluent: n-hexane/ethyl acetate) to give the title compound (0.45g).

REFERENCE EXAMPLE 28 (4-Methoxy-5-methyl-2-nitrophenyl)acetonitrile

To a solution of cyano-(4-methoxy-5-methyl-2-nitrophenyl)acetic acidmethyl ester in methanol (1.7 mL) was added 6 mol/L hydrochloric acid(1.7 mL), and this mixture was heated under reflux for 9 hours. Aftercooling to ambient temperature, this organic solvent was removed underreduced pressure and resulting mixture was extracted with ethyl acetate.The residue was purified by column chromatography on silica gel (eluent:n-hexane/ethyl acetate) to give the title compound (0.25 g).

REFERENCE EXAMPLE 29 6-Methoxy-5-methylindole

To a solution of (4-methoxy-5-methyl-2-nitrophenyl)acetonitrile (0.24 g)in a mixed solvent of tetrahydrofuran (2 mL) and n-butanol (2 mL) wasadded palladium-carbon powder (0.043 g) under an argon atmosphere andthis mixture was stirred at 60° C. under a hydrogen atmosphere for 36hours. The insoluble material was removed by filtration and the filtratewas concentrated under reduced pressure. The residue was purified bycolumn chromatography on silica gel (eluent: n-hexane/ethyl acetate) togive the title compound (0.13 g).

REFERENCE EXAMPLE 30 3-Cyano-6-methoxy-5-methylindole

The title compound (0.070 g) was prepared in a similar manner to thatdescribed in Reference Example 4 and Reference Example 5 using thecorresponding starting materials.

REFERENCE EXAMPLE 31 1-Methoxy-2-methyl-4-nitrobenzene

To a solution of 1-hydroxy-2-methyl-4-nitrobenzene (1.0 g) inN,N-dimethylformamide (10 mL) were added potassium carbonate (1.8 g) andiodomethane (1.3 g) at room temperature and this mixture was stirred atthe same temperature for 24 hours. This reaction mixture was poured intowater and this resulting mixture was extracted with ethyl acetate. Thisorganic layer was washed with water and brine, and dried over anhydrousmagnesium sulfate. The solvent was removed under reduced pressure togive the title compound (0.95 g).

REFERENCE EXAMPLE 32 (5-Methoxy-4-methyl-2-nitrophenyl)acetonitrile

To a solution of 1-methoxy-2-methyl-4-nitrobenzene (0.4 g) and(4-chlorophenoxy)acetonitrile (0.4 g) in N,N-dimethylformamide (10 mL)was added potassium tert-butoxide (0.3 g) under ice cooling and thismixture was stirred at the same temperature for 1 hours. This mixturewas poured into water and the resulting mixture was extracted with ethylacetate. This organic layer was washed with water and brine, and driedover anhydrous magnesium sulfate. The solvent was removed under reducedpressure. The residue was purified by column chromatography on silicagel (eluent: n-hexane/ethyl acetate) to give the title compound (0.2 g).

REFERENCE EXAMPLE 33 5-Methoxy-6-methyl-1H-indole

The title compound (0.065 g) was prepared in a similar manner to thatdescribed in Reference Example 29 using the corresponding startingmaterials.

REFERENCE EXAMPLE 34 5-Methoxy-6-methyl-1H-indole-3-carbonitrile

The title compound (0.05 g) was prepared in a similar manner to thatdescribed in Reference Example 4 and 5 using the corresponding startingmaterials.

REFERENCE EXAMPLE 35 5-Benzyloxy-6-chloro-1H-indole

To a solution of (5-benzyloxy-4-chloro-2-nitrophenyl)acetonitrile (4.170g) in ethanol (70 mL) was added platinum (IV) oxide (0.344 g) at roomtemperature and this mixture was stirred under a hydrogen atmosphere(30-35 psi) for 12 hours. To this reaction mixture were added aceticacid (7 mL) and water (7 mL), and this mixture was stirred under samecondition for 24 hours. After this reaction mixture was replaced underargon atmosphere, the insoluble material was removed by filtration. Tothis filtrate was added water and this resulting mixture was extractedwith diethyl ether. This organic layer was washed with brine, and driedover anhydrous magnesium sulfate, and filtered. The solvent was removedunder reduced pressure. The residue was purified by columnchromatography on silica gel (eluent: ethyl acetate/n-hexane=75/25) togive the title compound (0.629 g).

REFERENCE EXAMPLE 36 5-Benzyloxy-6-chloro-1H-indole-3-carbaldehyde

The title compound (0.270 g) was prepared in a similar manner to thatdescribed in Reference Example 4 using the corresponding startingmaterials.

REFERENCE EXAMPLE 37 5-Benzyloxy-6-chloro-1H-indole-3-carbonitrile

The title compound (0.267 g) was prepared in a similar manner to thatdescribed in Reference Example 5 using the corresponding startingmaterials.

REFERENCE EXAMPLE 38 Cyano-(4-fluoro-5-methyl-2-nitrophenyl)acetic acidbenzyl ester

A suspension of 1,4-difluoro-2-methyl-5-nitrobenzene (1.00 g),cyanoacetic acid benzyl ester (1.01 g) and potassium carbonate (1.76 g)in N,N-dimethylformamide (20.0 mL) was stirred at 60° C. for 1 day. Tothis reaction mixture was added 1 mol/L hydrochloric acid (25.4 mL), andthis mixture was extracted with diethyl ether. This organic layer waswashed with brine, and dried over anhydrous magnesium sulfate, andfiltered. The solvent was removed under reduced pressure. This residuewas washed with ethanol to give the title compound (1.54 g).

REFERENCE EXAMPLE 39 6-Fluoro-5-methyl-1H-indole

To a solution of cyano-(4-fluoro-5-methyl-2-nitrophenyl)acetic acidbenzyl ester (1.54 g), acetic acid (7 mL) and water (7 mL) in ethanol(15 mL) was added 10% palladium-carbon (0.154 g) under an argonatmosphere. This reaction mixture was stirred at room temperature for 60hours under a hydrogen atmosphere. After water was added to thisreaction mixture, hydrogen was exchanged by argon. The insolublematerial was removed by filtration, and this filtrate was extracted withdiethyl ether. This organic layer was washed with brine, and dried overanhydrous magnesium sulfate, and filtered. The solvent was removed underreduced pressure. The residue was purified by column chromatography onsilica gel (eluent: ethyl acetate/n-hexane=75/25) to give the titlecompound (0.536 g).

REFERENCE EXAMPLE 40 6-Fluoro-5-methyl-1H-indole-3-carbaldehyde

The title compound (0.577 g) was prepared in a similar manner to thatdescribed in Reference Example 4 using the corresponding startingmaterials.

REFERENCE EXAMPLE 41 6-Fluoro-5-methyl-1H-indole-3-carbonitrile

The title compound (0.544 g) was prepared in a similar manner to thatdescribed in Reference Example 5 using the corresponding startingmaterials.

REFERENCE EXAMPLE 42 6-Benzyloxy-5-methoxy-1H-indole

4-Benzyloxy-3-methoxybenzaldehyde (4.85 g) was added to nitric acid(d=1.42, 20 mL) in a dropwise manner over 1 hour at room temperature,and this mixture was stirred for 1 hour. This reaction mixture waspoured into ice water and the precipitated solid was collected byfiltration. This solid was washed with water, dried under reducedpressure at 50° C. to give 4-benzyloxy-5-methoxy-2-nitrobenzaldehyde(4.99 g). To this product was added acetic acid (50 mL), followed byadding nitromethane (3.19 g) and ammonium acetate (5.36 g), and thismixture was stirred for 5 hours at 100° C. This reaction mixture wasconcentrated under reduced pressure. To this residue was added water andthe precipitated solid was collected by filtration, and this solid waswashed with methanol, dried to give1-benzyloxy-2-methoxy-5-nitro-4-(2-nitrovinyl)benzene (4.03 g). To thiscompound were added benzene (96 mL), acetic acid (72 mL) and cyclohexane(24 mL), followed by adding silica gel (18 g) and iron powder (10.2 g),and this mixture was stirred at 100° C. for 1 hour. The insolublematerial was removed by filtration, and this filtrate was concentratedunder reduced pressure. The residue was purified by columnchromatography on silica gel (eluent: ethyl acetate/n-hexane=75/25) togive the title compound (1.06 g).

REFERENCE EXAMPLE 43 6-Benzyloxy-5-methoxy-1H-indole-3-carbaldehyde

The title compound was prepared in a similar manner to that described inReference Example 4 using the corresponding starting materials.

REFERENCE EXAMPLE 44 6-Benzyloxy-5-methoxy-1H-indole-3-carbonitrile

The title compound was prepared in a similar manner to that described inReference Example 5 using the corresponding starting materials.

REFERENCE EXAMPLES 45 to 47

The title compounds were prepared in a similar manner to that describedin Reference Example 29 using the corresponding starting materials.

REFERENCE EXAMPLE 48 Dimethyl-(4-nitro-2-trifluoromethylphenyl)amine

To a solution of 1-floro-4-nitro-2-trifluoromethylbenzene (2.0 g) intetrahydrofuran (20 mL) were added dimethyamine (0.64 g) and sodiumhydride (0.34 g) at room temperature, and this mixture was stirred at50° C. for 16 hours. This reaction mixture was poured into water, andthis mixture was extracted with ethyl acetate. This organic layer waswashed with water and brine, and dried over anhydrous magnesium sulfate.The solvent was removed under reduced pressure. The residue was purifiedby column chromatography on silica gel (eluent: n-hexane/ethyl acetate)to give the title compound (0.94 g).

REFERENCE EXAMPLE 49(5-Dimethylamino-2-nitro-4-trifluoromethylphenyl)acetonitrile

To a solution of dimethyl-(4-nitro-2-trifluoromethylphenyl)amine (0.95g) in N,N-dimethylformamide (20 mL) were added(4-chlorophenoxy)acetonitrile (0.75 g) and 1 mol/L potassiumtert-butoxide (4.5 mL, in tetrahydrofuran solution) under ice cooling,and this mixture was stirred at the same temperature for 1 hour. Thisreaction mixture was poured into water, and this mixture was extractedwith ethyl acetate. This organic layer was washed with water and brine,and dried over anhydrous magnesium sulfate. The solvent was removedunder reduced pressure. The residue was purified by columnchromatography on silica gel (eluent: n-hexane/ethyl acetate) to givethe title compound (0.11 g).

REFERENCE EXAMPLE 50 Dimethyl-(6-trifluoromethyl-1H-indol-5-yl)amine

To a solution of(5-dimethylamino-2-nitro-4-trifluoromethylphenyl)acetonitrile (0.058 g)in a mixed solvent of ethanol (1 mL), acetic acid (0.1 mL) and water(0.1 mL) was added palladium-carbon powder (0.0058 g), and this mixturewas stirred at 35° C. for 16 hours. The insoluble material was removedby filtration and the filtrate was concentrated under reduced pressureto give the title compound (0.058 g).

REFERENCE EXAMPLE 514-(5-Dimethylamino-6-trifluoromethylindol-1-yl)benzoic acid ethyl ester

The title compound was prepared in a similar manner to that described inReference Example 20 using the corresponding starting materials.

REFERENCE EXAMPLE 524-(3-Formyl-5-methylamino-6-trifluoromethylindol-1-yl)benzoic acid ethylester

To a solution of 4-(5-dimethylamino-6-trifluoromethylindol-1-yl)benzoicacid ethyl ester (0.054 g) in N,N-dimethylformamide (2 mL) was addedphosphoryl chloride (0.026 g) under ice cooling, and this mixture wasstirred at room temperature for 16 hours. To this mixture was added 2mol/L aqueous sodium hydroxide solution (5 mL), and this resultingmixture was stirred at 50° C. for 30 minutes. After cooling to ambienttemperature, 1 mol/L hydrochloric acid (10 mL) was added to thismixture, and the precipitated solid was collected by filtration. Thissolid was washed with water and n-hexane, dried under reduced pressureat 50° C. to give the title compound (0.026 g).

REFERENCE EXAMPLE 53

The title compound was prepared in a similar manner to that described inReference Example 29 using(3-benzyloxy-2,4-dimethyl-6-nitrophenyl)acetonitrile instead of(4-methoxy-5-methyl-2-nitrophenyl)acetonitrile.

REFERENCE EXAMPLES 54 to 55

The title compounds were prepared in a similar manner to that describedin Example 5 using the indole obtained in a similar manner to thatdescribed in Reference example 31 using Reference example 53 and thecorresponding starting materials.

REFERENCE EXAMPLES 56 to 63

The title compounds were prepared in a similar manner to that describedin Reference Example 5 using the corresponding starting materials.

EXAMPLE 1 4-(3-Cyano-5,6-difluoroindol-1-yl)-2-methoxymethoxybenzoicacid ethyl ester

To a solution of 3-cyano-5,6-difluoroindole (0.25 g) inN,N-dimethylformamide (10 mL) were added cesium carbonate (0.91 g),4-fluoro-2-methoxymethoxybenzoic acid ethyl ester (0.32 g), and thismixture was stirred at 75° C. overnight. This reaction mixture waspoured into water, and this resulting mixture was extracted with ethylacetate. This organic layer was washed with water and brine, and driedover anhydrous magnesium sulfate. The solvent was removed under reducedpressure. The residue was purified by column chromatography on silicagel (eluent: ethyl acetate/n-hexane=10/90-75/25) to give the titlecompound (0.12 g).

EXAMPLE 2 4-(3-Cyano-5,6-difluoroindol-1-yl)-2-hydroxybenzoic acid ethylester

To a solution of4-(3-cyano-5,6-difluoroindol-1-yl)-2-methoxymethoxybenzoic acid ethylester (0.12 g) in a mixed solvent of tetrahydrofuran (1.5 mL) andethanol (3 mL) was added 2 mol/L hydrochloric acid (1.0 mL), and thismixture was stirred at 70° C. overnight. After cooling to ambienttemperature, the precipitated solid was collected by filtration, andwashed with water and n-hexane, and dried under reduced pressure at 40°C. to give the title compound (0.074 g).

EXAMPLE 3 4-(3-Cyano-5,6-difluoroindol-1-yl)-2-hydroxybenzoic acid

To a solution of 4-(3-cyano-5,6-difluoroindol-1-yl)-2-hydroxybenzoicacid ethyl ester (0.074 g) in a mixed solvent of tetrahydrofuran (3.0mL) and ethanol (0.75 mL) were added 0.1 g/mL aqueous lithium hydroxidesolution (0.62 mL) and water (1.0 mL), and this mixture was stirred atroom temperature for 26 hours. To this reaction mixture was added 2mol/L hydrochloric acid (5 mL), this organic solvent was removed underreduced pressure. This resulting mixture was extracted with ethylacetate, this organic layer was washed with water, and dried overanhydrous magnesium sulfate. The solvent was concentrated under reducedpressure to give the title compounds (0.06 g).

EXAMPLE 4 4-(6-Benzyloxy-3-cyanoindol-1-yl)-2-methoxymethoxybenzoic acidethyl ester

The title compound (3.4 g) was prepared in a similar manner to thatdescribed in Example 1 using the corresponding starting materials.

EXAMPLE 5 4-(6-Benzyloxy-3-cyanoindol-1-yl)-2-hydroxybenzoic acid

The title compound was prepared in a similar manner to that described inExample 2 and Example 0.3 using the corresponding starting materials.

EXAMPLE 6 4-(3-Cyano-6-hydroxyindol-1-yl)-2-methoxymethoxybenzoic acidethyl ester

To a solution of4-(6-benzyloxy-3-cyanoindol-1-yl)-2-methoxymethoxybenzoic acid ethylester in a mixed solvent of ethyl acetate (60 mL) and methanol (60 mL)was added palladium-carbon powder (0.61 g) under argon atmosphere at 0°C. and this mixture was stirred at 40° C. under a hydrogen atmospherefor 3 hours. The insoluble material was removed by filtration, and thefiltrate was concentrated under reduced pressure to give the titlecompound (2.5 g)

EXAMPLE 74-[6-(2-Benzyloxycarbonylaminoethyloxy)-3-cyanoindol-1-yl]-2-methoxymethoxybenzoicacid ethyl ester

To a solution of 4-(3-cyano-6-hydroxyindol-1-yl)-2-methoxymethoxybenzoicacid ethyl ester (0.37 g) in N,N-dimethylformamide (10 mL) were added(2-bromoethyl)carbamic acid benzyl ester (0.39 g) and potassiumcarbonate (0.28 g), and this mixture was stirred at 50° C. overnight.This reaction mixture was poured into water, and the precipitated solidwas collected by filtration. This solid was washed with methanol, anddried to give the title compound (0.40 g).

EXAMPLE 84-[6-(2-Benzyloxycarbonylaminoethyloxy)-3-cyanoindol-1-yl]-2-hydroxybenzoicacid

To a solution of4-[6-(2-benzyloxycarbonylaminoethyloxy)-3-cyanoindol-1-yl]-2-methoxymethoxybenzoicacid ethyl ester (0.14 g) in a mixed solvent of ethanol (2.5 mL),tetrahydrofuran (5 mL), and water (2.5 mL) was added lithium hydroxidemono hydrate (0.03 g), and this mixture was stirred at room temperaturefor 3 hours. To this reaction mixture was added 2 mol/L hydrochloricacid (0.75 mL), and this mixture was stirred at 50° C. for 5 hours. Thisreaction mixture was treated 1 mol/L hydrochloric acid (5 mL), and thismixture was concentrated under reduced pressure until this solventvolume became one-third. The precipitated solid was collected byfiltration, and washed with water, methanol and ether to give the titlecompound (0.097 g)

EXAMPLE 9 4-[6-(2-Aminoethyloxy)-3-cyanoindol-1-yl]-2-hydroxybenzoicacid

To a solution of4-[6-(2-benzyloxycarbonylaminoethyloxy)-3-cyanoindol-1-yl]-2-hydroxybenzoicacid (0.087 g) in a mixed solvent ethyl acetate (2 mL) and methanol (2mL) was added palladium-carbon powder (0.016 g) under an argonatmosphere at 0° C., and this mixture was stirred at 40° C. under ahydrogen atmosphere for 3 hours. The insoluble material was removed byfiltration, and the filtrate was concentrated under reduced pressure.This obtained light yellow solid was washed with diethyl ether, dried togive the title compound (0.058 g).

EXAMPLE 104-[6-(2-Aminoethyloxy)-3-cyanoindol-1-yl]-2-methoxymethoxybenzoic acidethyl ester

To a solution of4-[6-(2-benzyloxycarbonylaminoethoylxy)-3-cyanoindol-1-yl]-2-methoxymethoxybenzoicacid ethyl ester (0.27 g) in a mixed solvent of ethyl acetate (5 mL) andmethanol (5 mL) was added palladium-carbon powder (0.05 g) under anargon atmosphere at 0° C., and this mixture was stirred at 40° C. undera hydrogen atmosphere for 3 hours. The insoluble material was removed byfiltration, and the filtrate was concentrated under reduced pressure.This obtained light yellow solid was washed with diethyl ether, dried togive the title compound (0.20 g).

EXAMPLE 114-[6-(2-Acetylaminoethyloxy)-3-cyanoindol-1-yl]-2-methoxymethoxybenzoicacid ethyl ester

To a solution of4-[6-(2-aminoethyloxy)-3-cyanoindol-1-yl]-2-methoxy-methoxy benzoic acidethyl ester (0.10 g) and triethylamine (0.076 g) in dichloromethane (5mL) was added acetyl chloride (0.049 g) at room temperature, and thismixture was stirred at room temperature for 12 hours. This reactionmixture was concentrated under reduced pressure. The residue waspurified by column chromatography on silica gel (eluent:dichloromethane:methanol=10:1) to give the title compound (0.083 g).

EXAMPLE 124-[6-(2-Acetylaminoethyloxy)-3-cyanoindol-1-yl]-2-hydroxybenzoic acid

The title compound (0.039 g) was prepared in a similar manner to thatdescribed in Example 8 using the corresponding starting materials.

EXAMPLE 13 4-(5-Bromo-3cyanoindol-1yl)benzoic acid ethyl ester

To a solution of 5-bromo-3-cyanoindole (2.0 g) in N,N-dimethylformamide(50 mL) were added cesium carbonate (7.4 g) and 4-fluorobenzoic acidethyl ester (3.0 g), and this mixture was stirred at 80° C. for 48hours. This reaction mixture was poured into water, and the precipitatedsolid was collected by filtration. This solid was washed with water,dried under reduced pressure at 50° C. to give the title compound (1.8

EXAMPLE 14 4-[3-Cyano-5-(4-methoxyphenyl)indol-1-yl]benzoic acid ethylester

A mixture of 4-(5-bromo-3cyanoindol-1 yl)benzoic acid ethyl ester (0.1g), 4-methoxyphenylboronic acid (0.066 g), potassium carbonate (0.09 g)in a mixed solvent of 1,2-dimethoxyethane (3 mL), ethanol (0.5 mL) andwater (0.5 mL) was stirred in the presence oftetrakis(triphenylphosphine) palladium catalyst at 90° C. for 18 hours.This reaction mixture was poured into water, and the precipitated solidwas collected by filtration. This solid was washed with water, driedunder reduced pressure at 50° C. to give the title compound (0.098 g).

EXAMPLE 15 4-[3-Cyano-5-(4-methoxyphenyl)indol-1-yl]benzoic acid

The title compound (0.081 g) was prepared in a similar manner to thatdescribed in Example 3 using the corresponding starting materials.

EXAMPLE 16 4-{5-[(E)-2-Ethoxycarbonylvinyl]-3-cyanoindol-1-yl}benzoicacid

A solution of 4-(5-bromo-3-cyanoindol-1-yl)benzoic acid ethyl ester (0.1g), acrylic acid ethyl ester (0.11 g) and triethylamine (0.082 g) inN,N-dimethylformamide (2 mL) was stirred in the presence of palladium(II) acetate (0.0061 g) and triphenylphosphine (0.014 g) at 100° C. for30 hours. This reaction mixture was poured into water, and thisresulting mixture was extracted with ethyl acetate twice. This organiclayer was washed with brine, and dried over anhydrous magnesium sulfate.The solvent was concentrated under reduced pressure. The residue waspurified by column chromatography on silica gel, (eluent: ethylacetate/n-hexane=10/90-75/25) to give the title compound (0.035 g).

EXAMPLE 17 4-[5-((E)-2-Carboxyvinyl)-3-cyanoindol-1-yl]benzoic acid

The title compound was prepared in a similar manner to that described inExample 3 using the corresponding starting materials.

EXAMPLE 18 4-(4-Benzyloxy-3-cyanoindol-1-yl)benzoic acid ethyl ester

The title compound (0.16 g) was prepared in a similar manner to thatdescribed in Example 13 using the corresponding starting materials.

EXAMPLE 19 4-(4-Benzyloxy-3-cyanoindol-1-yl)benzoic acid

To a solution of 4-(4-benzyloxy-3-cyanoindol-1-yl)benzoic acid ethylester (0.16 g) in ethanol (2 mL) was added 2 mol/L aqueous sodiumhydroxide solution (0.4 mL), and this mixture was stirred at 50° C.overnight. Ethanol was removed under reduced pressure, and to thisreaction mixture was added 2 mol/L hydrochloric acid (3 mL). Theprecipitated solid was collected by filtration, and this solid waswashed with water and n-hexane to give the title compound (0.11 g).

EXAMPLE 20 4-(3-Cyano-6-nitroindol-1 yl)benzoic acid ethyl ester

To a solution of 4-(6-nitroindol-1-yl)benzoic acid ethyl ester (0.53 g)in N,N-dimethylformamide (6 mL) was added phosphoryl chloride (0.31 g)under ice cooling and this mixture was stirred at 70° C. overnight.After cooling to ambient temperature, to this reaction mixture was added2 mol/L aqueous sodium hydroxide solution and this mixture was stirredat 30 minutes. This reaction mixture was poured into 1 mol/Lhydrochloric acid, and the precipitated solid was collected byfiltration, and washed with water and n-hexane, and dried under reducedpressure at 40° C. to give 4-(3-formyl-6-nitroindol-1-yl)benzoic acidethyl ester (0.46 g). To a solution of this aldehyde (0.46 g) intetrahydrofuran (10 mL) were added hydroxylamine hydrochloride (0.19 g)and pyridine (0.43 g) at room temperature, and this mixture was stirredat 80° C. for 8 hours. To this reaction mixture was added aceticanhydride (0.42 g) at 80° C., this mixture was stirred at sametemperature overnight. After cooling to ambient temperature, to thisreaction mixture was added 1 mol/L hydrochloric acid, and theprecipitated solid was collected by filtration. This solid was washedwith water, n-hexane and diethyl ether to give the title compound (0.13g).

EXAMPLE 21 4-(6-Amino-3-cyanoindol-1-yl)benzoic acid ethyl ester

To a solution of 4-(3-cyano-6-nitroindol-1 yl)benzoic acid ethyl ester(0.11 g) in a mixed solvent of tetrahydrofuran (2 mL) and methanol (2mL) was added palladium-carbon powder (0.04 g) under an argonatmosphere, and this mixture was stirred at room temperature under ahydrogen atmosphere for 7 hours. The insoluble material was removed byfiltration, and the filtrate was concentrated under reduced pressure togive the title compound (0.070 g).

EXAMPLE 22 4-(3-Cyano-6-methanesulfonylaminoindol-1-yl)benzoic acidethyl ester

To a solution of 4-(5-amino-3-cyanoindol-1-yllbenzoic acid ethyl ester(0.070 g) in dichloromethane (2 mL) were added methanesulfonyl chloride(0.035 g) and pyridine (0.036 g) at room temperature, and this mixturewas stirred at room temperature overnight. This reaction mixture waspoured into 1 mol/L hydrochloric acid, this resulting mixture wasextracted with ethyl acetate. This organic layer was washed with water,and dried over anhydrous magnesium sulfate. The solvent was removedunder reduced pressure. The residue was purified by columnchromatography on silica gel (eluent: ethylacetate/n-hexane=10/90-75/25) to give the title compound (0.046 g).

EXAMPLE 23 4-(3-Cyano-6-methanesulfonylaminoindol-1-yl)benzoic acid

The title compound (0.040 g) was prepared in a similar manner to thatdescribed in Example 3 using the corresponding starting materials.

EXAMPLE 24 4-(5-Benzyloxy-3-cyanoindol-1-yl)benzoic acid ethyl ester

The title compound was prepared in a similar manner to that described inExample 13 using the corresponding starting materials.

EXAMPLE 25 4-(5-Hydroxy-3-cyanoindol-1-yl)benzoic acid ethyl ester

The title compound was prepared in a similar manner to that described inExample 6 using the corresponding starting materials.

EXAMPLE 26 4-[3-Cyano-5-(thiophen-2-ylmethyloxy)indol-1-yl]benzoic acidethyl ester

To a solution of 4-(5-hydroxy-3-cyanoindol-1-yl)benzoic acid ethyl esterand thiophene-2-methanol (0.057 g) and triphenylphosphine (0.012 g) intetrahydrofuran (2.5 mL) was added diisopropylcarbodiimide (40% toluenesolution, 0.18 mL) at room temperature, and this mixture was stirred for3 hours. This reaction mixture was concentrated under reduced pressure.This residue was purified by column chromatography on silica gel(eluent: ethyl acetate/n-hexane=1/3) to give the title compound (0.10g).

EXAMPLE 27 4-[3-Cyano-5-(thiophen-2-ylmethyloxy)indol-1-yl]benzoic acid

The title compound (0.01 g) was prepared in a similar manner to thatdescribed in Example 3 using the corresponding starting materials.

EXAMPLE 28 4-(3-Cyano-5-benzyloxycarbonylindol-1-yl)benzoic acid ethylester

The title compound (0.24 g) was prepared in a similar manner to thatdescribed in Example 13 using the corresponding starting materials.

EXAMPLE 29 4-(5-Carboxy-3-cyanoindol-1-yl)benzoic acid

The title compound (0.050 g) was prepared in a similar manner to thatdescribed in Example 3 using the corresponding starting materials.

EXAMPLE 30 4-(5-Carboxy-3-cyanoindol-1-yl)benzoic acid ethyl ester

To a solution of 4-(3-cyano-5-benzyloxycarbonylindol-1-yl)benzoic acidethyl ester (0.16 g) in a mixed solvent of methanol (5 mL) andtetrahydrofuran (5 mL) was added palladium-carbon powder (0.03 g) at 0°C. under an argon atmosphere, and this mixture was stirred at roomtemperature under a hydrogen atmosphere for 3 hours. The insolublematerial was removed by filtration, and the filtrate was concentratedunder reduced pressure to give the title compound (0.057 g).

EXAMPLE 31 4-(3-Cyano-5-hydroxymethylindol-1-yl)benzoic acid ethyl ester

To a solution of 4-(5-carboxy-3-cyanoindol-1yl)benzoic acid ethyl ester(0.057 g) in tetrahydrofuran (2 mL) was added borane-tetrahydrofurancomplex (1.2 mol/L tetrahydrofuran solution 0.2 mL) at 0° C. and thismixture was stirred at room temperature for 2 hours. To this reactionmixture was added a saturated aqueous sodium bicarbonate solution, thismixture was extracted with diethyl ether. This organic layer was washedwith brine, and dried over anhydrous magnesium sulfate. The solvent wasremoved under reduced pressure. The residue was purified by columnchromatography on silica gel (eluent: ethyl acetate/n-hexane=1/1) togive the title compound (0.032 g).

EXAMPLE 32 4-(3-Cyano-5-hydroxymethylindol-1-yl)benzoic acid

The title compound (0.029 g) was prepared in a similar manner to thatdescribed in Example 3 using the corresponding starting materials.

EXAMPLE 33 4-(3-Cyano-5-dimethylaminocarbonylindol-1-yl)benzoic acidethyl ester

To a solution of 4-(5-carboxy-3-cyanoindol-1yl)benzoic acid ethyl ester(0.084 g), dimethylamine hydrochloride (0.061 g), triethylamine (0.13 g)and 4-dimethylaminopyridine (0.006 g) in dichloromethane (2.5 mL) wasadded N-ethyl-N′-3-dimethylaminopropylcarbodiimide (0.058 g) at roomtemperature, and this mixture was stirred at room temperature overnight.This reaction mixture was poured into 1 mol/L hydrochloric acid, andthis mixture was extracted with ethyl acetate. This organic layer waswashed with a saturated aqueous sodium bicarbonate solution and brine,dried over anhydrous magnesium sulfate. The solvent was removed underreduced pressure. The residue was purified by column chromatography onsilica gel (eluent: ethyl acetate/n-hexane=1/2) to give the titlecompound (0.020 g).

EXAMPLE 34 4-(3-Cyano-5-dimethylaminocarbonylindol-1-yl)benzoic acid

The title compound (0.0025 g) was prepared in a similar manner to thatdescribed in Example 3 using the corresponding starting materials.

EXAMPLE 35 5-(3-Cyanoindol-1-yl)furan-2-carboxylic acid

To a suspension of 1-(5-formylfuran-2-yl)-1H-indole-3-carbonitrile(0.085 g) in methanol (4 mL) and tetrahydrofuran. (4 mL) were addedsilver oxide (0.1 g) and 2 mol/L aqueous sodium hydroxide solution (0.27mL), this mixture was stirred at room temperature for 6 hours. Theinsoluble material of reaction mixture was removed by filtration, andthe filtrate was concentrated under reduced pressure. To this residuewere added water (15 mL) and 2 mol/L hydrochloric acid solution (2 mL),this mixture was extracted with ethyl acetate. This organic layer waswashed with brine, dried over anhydrous magnesium sulfate. The solventwas removed under reduced pressure. The residue was purified by columnchromatography on silica gel (eluent: dichloromethane/methanol=10/1) togive the title compound (0.023 g).

EXAMPLE 36 3-(3-Cyanoindol-1-yl)benzoic acid ethyl ester

To a solution of 1H-indole-3-carbonitrile (0.28 g) in dimethyl sulfoxide(3 mL) were added 3-iodobenzoic acid ethyl ester (0.61 g), cesiumcarbonate (0.65 g), copper iodide (0.038 g) and N,N-dimethyl grycine(0.041 g), this mixture was stirred at 75° C. for 3 days. To thisreaction mixture was added ethyl acetate, the insoluble material wasremoved by filtration and this filtrate was concentrated under reducedpressure. To this residue was added water, the precipitated solid wascollected by filtration, and washed with water and n-hexane, and driedunder reduced pressure at 40° C. to give the title compound (0.38 g).

EXAMPLE 37 3-(3-Cyanoindol-1-yl)benzoic acid

The title compound (0.30 g) was prepared in a similar manner to thatdescribed in Example 3 using the corresponding starting materials.

EXAMPLE 38 2-(3-Cyanoindol-1-yl)isonicotinic acid ethyl ester

A mixture of 1H-indole-3-carbonitrile (0.1 g), 2-bromoisonicotinic acidethyl ester (0.16 g), potassium phosphate (0.27 g),(1R,2R)-(−)-N,N′-dimethylcyclohexane-1,2-diamine (0.017 g), copperiodide (0.006 g) and toluene (0.7 mL) was stirred at 110° C. for 38hours. The insoluble material was removed by filtration, and thisfiltrate was concentrated under reduced pressure. The residue waspurified by column chromatography on silica gel (eluent: ethylacetate/n-hexane=10/90 to 66/34) to give the title compound (0.061 g).

EXAMPLE 39 2-(3-Cyanoindol-1-yl)isonicotinic acid

The title compound (0.038 g) was prepared in a similar manner to thatdescribed in Example 8 using the corresponding starting materials.

EXAMPLE 40 4-(3-Cyanoindol-1-yl)-2-nitrobenzoic acid methyl ester

The title compound was prepared in a similar manner to that described inExample 1 using the corresponding starting materials.

EXAMPLE 41 4-(3-Cyanoindol-1-yl)-2-nitrobenzoic acid

The title compound was prepared in a similar manner to that described inExample 3 using the corresponding starting materials.

EXAMPLE 42 2-Amino-4-(3-cyanoindol-1-yl)benzoic acid

To a solution of 4-(3-cyanoindol-1-yl)-2-nitrobenzoic acid (0.012 g) ina mixed solvent of ethanol (1 mL), water (0.5 mL) and tetrahydrofuran(0.5 mL) were added zinc powder (0.041 g) and ammonium chloride (0.004g) at room temperature, and this mixture was stirred at 80° C. for 2.5hours. After cooling to ambient temperature, to this reaction mixturewas added ethyl acetate. This insoluble material was removed byfiltration and this filtrate was washed with brine, dried over anhydrousmagnesium sulfate. The solvent was removed under reduced pressure togive the title compound (0.003 g).

EXAMPLE 43 2-Acetoxy-(3-cyanoindol-1-yl)benzoic acid

To a suspension of 4-(3-cyanoindol-1-yl)-2-hydroxybenzoic acid inpyridine (0.5 mL) was added acetic anhydride (0.1 mL) at 0° C., and thismixture was stirred at room temperature for 1 hour. This reactionmixture was poured into 1 mol/L hydrochloric acid, and this mixture wasextracted with ethyl acetate. This organic layer was washed with brine,dried over anhydrous magnesium sulfate. The solvent was removed underreduced pressure to give the title compound (0.047 g).

EXAMPLE 44 2-(3-Cyanoindol-1-yl)nicotinic acid ethyl ester

The title compound was prepared in a similar manner to that described inReference Example 13 using 6-chloronicotinic acid ethyl ester instead of4-fluorobenzoic acid ethyl ester.

EXAMPLE 45 2-(3-Cyanoindol-1-yl)nicotinic acid

The title compound was prepared in a similar manner to that described inExample 3 using the corresponding starting materials.

EXAMPLE 46 2-(3-Cyanoindol-1-yl)-4-methylthiazole-5-carboxylic acidethyl ester

The title compound was prepared in a similar manner to that described inReference Example 13 using 2-chloro-4-methylthiazole-5-carboxylic acidethyl ester instead of 4-fluorobenzoic acid ethyl ester.

EXAMPLE 47 2-(3-Cyanoindol-1-yl)-4-methylthiazole-5-carboxylic acid

The title compound was prepared in a similar manner to that described inExample 3 using the corresponding starting materials.

EXAMPLES 48 to 55

The compounds of Examples 48 to 55 were prepared in a similar manner tothat described in Example 13 using the corresponding starting materials.

EXAMPLES 56 to 65

The compounds of Examples 56 to 65 were prepared in a similar manner tothat described in Example 7 using the corresponding starting materials.

EXAMPLES 66 to 76

The compounds of Examples 66 to 76 were prepared in a similar manner tothat described in Example 14 using the corresponding starting materials.

EXAMPLES 77 to 81

The compounds of Examples 77 to 81 were prepared in a similar manner tothat described in Example 33 using the corresponding starting materials.

EXAMPLES 82 to 84

The compounds of Examples 82 to 84 were prepared in a similar manner tothat described in Example 26 using the corresponding starting materials.

EXAMPLES 85 to 86

The compounds of Example 85 to 56 were prepared in a similar manner tothat described in Example 44 using the corresponding starting materials.

EXAMPLE 87

The compound of Example 87 was prepared in a similar manner to thatdescribed in Example 13 using the corresponding starting materials.

EXAMPLE 88

The compound of Example 88 was prepared in a similar manner to thatdescribed in Example 20 using the corresponding starting materials.

EXAMPLES 89 to 107

The compounds of Examples 89 to 107 were prepared in a similar manner tothat described in Example 1 using the corresponding starting materials.

EXAMPLES 108 to 109

The compounds of Examples 108 to 109 were prepared in a similar mannerto that described in Example 6 using the corresponding startingmaterials.

EXAMPLES 110 to 134

The compounds of Examples 110 to 134 were prepared in a similar mannerto that described in Example 7 using the corresponding startingmaterials.

EXAMPLES 135 to 136

The compounds of Examples 135 to 136 were prepared in a similar mannerto that described in Example 26 using the corresponding startingmaterials.

EXAMPLE 137

The compound of Example 137 was prepared in a similar manner to thatdescribed in Example 10 using the corresponding starting materials.

EXAMPLES 138 to 140

The compounds of Examples 138 to 140 were prepared in a similar mannerto that described in Example 11 using the corresponding startingmaterials.

EXAMPLES 141 to 187

The compounds of Examples 141 to 187 were prepared in a similar mannerto that described in Example 3 using the corresponding startingmaterials.

EXAMPLES 188 to 225

The compounds of Examples 188 to 225 were prepared in a similar mannerto that described in Example 2 and Example 3 using the correspondingstarting materials.

EXAMPLES 226 to 227

The compounds of Examples 226 to 227 were prepared in a similar mannerto that described in Example 8 using the corresponding startingmaterials.

EXAMPLES 228 to 234

The compounds of Examples 228 to 234 were prepared in a similar mannerto that described in Example 2 and Example 3 using the correspondingstarting materials.

EXAMPLE 235

The compound of Example 235 was prepared in a similar manner to thatdescribed in Example 8 using the corresponding starting materials.

EXAMPLES 236 to 237

The compounds of Examples 236 to 237 were prepared in a similar mannerto that described in Example 2 and Example 3 using the correspondingstarting materials.

EXAMPLES 238 to 240

The compounds of Examples 238 to 240 were prepared in a similar mannerto that described in Example 8 using the corresponding startingmaterials.

EXAMPLE 241

The compound of Example 235 was prepared in a similar manner to thatdescribed in Example 3 using the corresponding starting materials.

EXAMPLE 242 4-(3-Cyano-5-methoxy-6-methylindol-1-yl)benzoic acid ethylester

The title compound was prepared in a similar manner to that described inExample 13 using the corresponding starting materials.

EXAMPLE 243 4-(5-Benzyloxy-6-chloro-3-cyanoindol-1-yl)benzoic acid ethylester

The title compound (0.31 g) was prepared in a similar manner to thatdescribed in Example 13 using the corresponding starting materials.

EXAMPLE 244 4-(6-Chloro-3-cyano-5-hydroxyindol-1-yl)benzoic acid ethylester

To a solution of 4-(5-benzyloxy-6-chloro-3-cyanoindol-1-yl)benzoic acidethyl ester (0.310 g) in dichloromethane (7 mL) was added borontribromide (1 mol/L dichloromethane solution) (0.860 mL) under icecooling, and this mixture was stirred at the same temperature for 1hour. To this reaction mixture was added water, this mixture wasextracted with ethyl acetate. This organic layer was washed with brine,dried over anhydrous magnesium sulfate and filtered. This filtrate wasremoved under reduced pressure. The residue was washed with diethylether to give the title compound (0.181 g).

EXAMPLE 245 4-(6-Chloro-3-cyano-5-methoxyindol-1-yl)benzoic acid ethylester

The title compound was prepared in a similar manner to that described inExample 31 using the corresponding starting materials.

EXAMPLE 2464-(6-Chloro-3-cyano-5-trifluoromethanesulfonyloxyindol-1-yl)benzoic acidethyl ester

To a solution of 4-(6-chloro-3-cyano-5-hydroxyindol-1-yl)benzoic acidethyl ester (0.079 g) and pyridine (0.056 mL) in dichloromethane (2.3mL) was added trifluoromethanesulfonic anhydride (0.058 mL) under icecooling, and this mixture was stirred at the same temperature for 1hour. To this reaction mixture was added 1 mol/L hydrochloric acid(0.370 mL) and water. After separating organic layer, this organicsolvent was removed under reduced pressure to give the title compound(0.103 g).

EXAMPLE 247 4-(6-Chloro-3-cyano-5-methylindol-1-yl)benzoic acid ethylester

To a solution of4-(6-chloro-3-cyano-5-trifluoromethanesulfonyloxyindol-1-yl)benzoic acidethyl ester (0.103 g), trimethylboroxine (0.033 g) and tripotassiumphosphate (0.070 g) in dioxane (2.0 mL) was addedtetrakis(triphenylphosphine) palladium catalyst (0.038 g), and thismixture was stirred at 80° C. for 1 day. The reaction mixture waspurified by column chromatography on silica gel (eluent: ethylacetate/n-hexane=75/25) to give the title compound (0568 g).

EXAMPLE 248 4-(3-Cyano-6-fluoro-5-methylindol-1-yl)benzoic acid ethylester

The title compound (0.117 g) was prepared in a similar manner to thatdescribed in Example 13 using the corresponding starting materials.

EXAMPLE 249 6-(3-Cyano-6-fluoro-5-methylindol-1-yl)nicotinic acid ethylester

The title compound (0.152 g) was prepared in a similar manner to thatdescribed in Example 44 using the corresponding starting materials.

EXAMPLE 2504-(3-Cyano-6-fluoro-5-methylindol-1-yl)-2-methoxymethoxybenzoic acidethyl ester

The title compound (0.116 g) was prepared in a similar manner to thatdescribed in Example 1 using the corresponding starting materials.

EXAMPLE 251 4-(6-Benzyloxy-3-cyano-5-methoxyindol-1-yl)benzoic acidethyl ester

The title compound was prepared in a similar manner to that described inExample 13 using the corresponding starting materials.

EXAMPLE 252 4-(3-Cyano-6-hydroxy-5-methoxyindol-1-yl)benzoic acid ethylester

The title compound was prepared in a similar manner to that described inExample 6 using the corresponding starting materials.

EXAMPLE 253 4-(3-Cyano-6-cyclopropyl-5-methoxyindol-1-yl)benzoic acidethyl ester

To a solution of 4-(3-cyano-6-hydroxy-5-methoxyindol-1-yl)benzoic acidethyl ester (0.195 g) and pyridine (0.138 g) in dichloromethane (2.3 mL)was added trifluoromethanesulfonic anhydride (0.246 g) under icecooling, and this mixture was stirred at the same temperature for 1hour. To this reaction mixture was added 1 mol/L hydrochloric acid(0.370 mL) and water, and this organic layer was separated. This organicsolvent was concentrated under reduced pressure to give4-(3-cyano-5-methoxy-6-trifluoromethanesulfonyloxyindol-1-yl)benzoicacid ethyl ester (0.238 g). After to this product (0.070 g) was addedtoluene (1.5 mL), to this mixture was added cyclopropylboronic acid(0.016 g), potassium carbonate (0.031 g) andtetrakis(triphenylphosphine) palladium (0) (0.026 g), and this mixturewas stirred at 80° C. for 1 day. The reaction mixture was purified bycolumn chromatography on silica gel (eluent: ethylacetate/n-hexane=75/25) to give the title compound (0.037 g).

EXAMPLE 254 4-(Cyano-5-hydroxy-6-methylindol-1-yl)benzoic acid ethylester

The title compound was prepared in a similar manner to that described inExample 244 using 4-(3-cyano-5-methoxy-6-methylindol-1-yl)benzoic acidethyl ester.

EXAMPLE 255 4-(3-Cyano-5,6-dimethylindol-1-yl)benzoic acid ethyl ester

The title compound was prepared in a similar manner to that described inExample 246 and Example 247 using4-(cyano-5-hydroxy-6-methylindol-1-yl)benzoic acid ethyl ester.

EXAMPLE 256

The title compound was prepared in a similar manner to that described inExample 13 using the corresponding starting materials.

EXAMPLE 257 4-(3-cyano-6-fluoro-5-hydroxyindol-1-yl)benzoic acid

To a solution of 4-(3-cyano-6-fluoro-5-methoxyindol-1-yl)benzoic acidethyl ester (1.2 g) in dichloromethane (20 mL) was added borontribromide (1.0 mol/L dichloromethane solution) (10 mL) in a dropwisemanner under ice cooling, and this mixture was stirred at roomtemperature for 12 hours. This reaction mixture was poured into water,and this mixture was extracted with ethyl acetate, concentrated underreduced pressure to give the title compound (0.44 g).

EXAMPLE 258 4-[3-Cyano-6-fluoro-5-(2-methoxyethoxy)indol-1-yl]benzoicacid 2-methoxyethyl ester

To a solution of 4-(3-cyano-6-fluoro-5-hydroxyindol-1-yl)benzoic acid(0.06 g) in N,N-dimethylformamide (2 mL) were added1-bromo-2-methoxyethane (0.14 g) and potassium carbonate (0.13 g) atroom temperature, this mixture was stirred at the same temperature for16 hours. This reaction mixture was poured into water, and this mixturewas extracted with ethyl acetate. This organic layer was washed withwater and brine, dried over anhydrous magnesium sulfate. The solvent wasremoved under reduced pressure. The residue was purified by columnchromatography on silica gel (eluent: ethyl acetate/n-hexane) to givethe title compound (0.79 g).

EXAMPLES 259 to 264

The title compounds were prepared in a similar manner to that describedin Example 13 using the corresponding starting materials.

EXAMPLE 265

The title compound was prepared in a similar manner to that described inExample 245 using the corresponding starting materials.

EXAMPLE 266

The title compound was prepared in a similar manner to that described inExample 252 using the corresponding starting materials.

EXAMPLES 267 to 270

The title compounds were prepared in a similar manner to that describedin Example 1 using the corresponding starting materials.

EXAMPLE 271

The title compound was prepared in a similar manner to that described inExample 244 using the corresponding starting materials.

EXAMPLES 272 to 277

The title compounds were prepared in a similar manner to that describedin Example 1 using the corresponding starting materials.

EXAMPLE 278

The title compound was prepared in a similar manner to that described inExample 252 using the corresponding starting materials.

EXAMPLE 279

The title compound was prepared in a similar manner to that described inExample 1 using the corresponding starting materials and2,4-difluoro-6-methoxymethoxy benzoic acid ethyl ester instead of4-fluoro-2-methoxymethoxy benzoic acid ethyl ester.

EXAMPLES 280 to 282

The title compounds were prepared in a similar manner to that describedin Example 258 using the corresponding starting materials.

EXAMPLE 283 4-(3-Cyano-5-dimethylamino-6-trifluoromethylindol-1-yl)benzoic acid ethyl ester

To a solution of4-(3-formyl-5-methylamino-6-trifluoromethylindol-1-yl)benzoic acid ethylester (0.026 g) in tetrahydrofuran (1 mL) was added hydroxylaminehydrochloride (0.0067 g) and pyridine (0.02 g), and this mixture wasstirred at 60° C. for 4 hours. After cooling to ambient temperature,acetic anhydride (0.013 g) was added to reaction mixture and thismixture was stirred at 60° C. for 12 hours. This reaction mixture waspoured into water, and the precipitated solid was collected byfiltration. This solid was washed with water and n-hexane, dried underreduced pressure at 50° C. to give the title compound (0.026 g).

EXAMPLES 284 to 291

The title compounds were prepared in a similar manner to that describedin Example 3 using the corresponding starting materials.

EXAMPLE 292

The title compound was prepared in a similar manner to that described inExample 257 using the corresponding starting materials.

EXAMPLES 293 to 308

The title compounds were prepared in a similar manner to that describedin Example 3 using the corresponding starting materials.

EXAMPLE 309

After the corresponding carboxylic acid was prepared in a similar mannerto that described in Example 3, to this product was added 2 mol/Lhydrochloric acid until the pH became 1, and this mixture was stirredovernight. The precipitated solid was collected by filtration to givethe title compound.

EXAMPLES 310 to 321

The title compounds were prepared in a similar manner to that describedin Example 309 using the corresponding starting materials.

EXAMPLE 322

The title compound was prepared in a similar manner to that described inExample 2 and Example 3 using the corresponding starting materials.

EXAMPLE 323

The title compound was prepared in a similar manner to that described inExample 6 using the corresponding starting materials.

EXAMPLE 324

The title compound was prepared in a similar manner to that described inExample 309 using the corresponding starting materials, followed byalkylation in a similar manner to that described in Example 7.

EXAMPLE 325

The title compound was prepared in a similar manner to that described inExample 309 using the corresponding starting materials.

EXAMPLE 326

The title compound was prepared in a similar manner to that described inExample 324 using the corresponding starting materials.

EXAMPLE 327

The title compound was prepared in a similar manner to that described inExample 309 using the corresponding starting materials.

EXAMPLE 328

The title compound was prepared in a similar manner to that described inExample 41 and Example 21 using the corresponding starting materials.

Tables 1 to 3 and 42 to 45 show the chemical structures and ¹H-NMR dataof the above compounds of Reference Examples 1 to 23 and 24 to 53, Table46 shows the chemical structures of Reference Examples 54 to 63, Tables4 to 41, 47 to 49 and 53 to 59 show the chemical structures and ¹H-NMRdata of the above compounds of Examples 1 to 241, 242 to 258 and 284 to328, Tables 50 to 52 show the chemical structures of Examples 259 to283, respectively.

The abbreviations in these Tables: “Ref No.”, “Ex No.”, “Strc” and“Sols”, represent Reference Example number, Example number, chemicalstructure and measurement solvent of ¹H-NMR, respectively.

TABLE 1 Ref No. Strc (Solv) ¹H-NMR δ ppm: 1

(CDCl3) 1.41 (3H, t, J = 7.2 Hz), 4.41 (2H, q, J = 7.2 Hz), 6.55-6.65(1H, m), 6.67 (1H, dd, J = 10.4 Hz, 2.6 Hz), 7.86 (1H, dd, J = 9.0 Hz,6.6 Hz), 11.08 (1H, d, J = 2.5 Hz) 2

(CDCl3) 1.37 (3H, t, J = 7.0 Hz), 3.52 (3H, s), 4.35 (2H, q, J = 7.0Hz), 5.25 (2H, s), 6.07- 6.78 (1H, m), 6.94 (1H, dd, J = 2.4, 10.8 Hz),7.83 (1H, d, J = 7.0, 8.9 Hz) 3

(CDCl3) 3.52 (3H, s), 3.88 (3H, s), 5.25 (2H, s), 6.70-6.80 (1H, m),6.90-7.00 (1H, m), 7.75-7.95 (1H, m), 4

(DMSO-d6) 7.58 (1H, dd, J = 10.9 Hz, 7.0 Hz), 7.94 (1H, dd, J = 10.9 Hz,8.0 Hz), 8.37 (1H, s) 9.92 (1H, s), 12.28 (1H, brs.) 5

(DMSO-d6) 7.61 (1H, dd, J = 10.7 Hz, 7.0 Hz), 7.69 (1H, dd, J = 10.6 Hz,7.7 Hz), 8.32 (1H, s), 12.34 (1H, brs.) 6

(DMSO-d6) 7.05-7.20 (2H, m), 7.65-7.75 (2H, m), 8.62 (1H, s) 7

(DMSO-d6) 7.30-8.35 (9H, m), 12.2 (1H, brs.) 8

(DMSO-d6) 5.38 (2H, s), 7.25-7.55 (5H, m), 7.62 (1H, d, J = 8.7 Hz),7.85-7.95 (1H, m), 8.44 (1H, s), 8.80 (1H, s), 9.98 (1H, s), 12.4 (1H,s) 9

(CDCl3) 5.42 (2H, d), 7.30-7.55 (6H, m), 7.80 (1H, d, J = 2.9 Hz), 8.08(1H, dd, J = 8.7 Hz, 1.5 Hz), 8.50-8.65 (1H, m), 8.93 (1H, brs.) 10 

(DMSO-d6) 2.32 (3H, s), 5.11 (2H, s), 5.34 (2H, s), 7.15-7.70 (13H, m)

TABLE 2 Ref No. Strc (Solv) ¹H-NMR δ ppm: 11

(CDCl3) 2.28 (3H, s), 4.70 (2H, s), 5.10 (2H, s), 6.80-7.20 (3H, m),7.25-7.50 (5H, m) 12

(CDCl3) 2.36 (3H, s), 5.15 (2H, s), 7.30- 7.50 (8H, m), 9.92 (1H, s) 13

(DMSO-d6) 2.28 (3H, s), 5.22 (2H, s), 7.25- 7.50 (6H, m), 7.64 (1H, s),10.13 (1H, s) 14

(CDCl3) 2.24 (3H, s), 3.85 (3H, s), 4.82 (2H, s), 5.06 (2H, s), 6.34(1H, brs.), 7.07 (1H, s), 7.20-7.45 (12H, m) 15

(CDCl3) 2.35-2.45 (3H, m), 3.92 (3H, s), 5.11 (2H, s), 7.08 (1H, s),7.10 (1H, dd, J = 2.0 Hz, 0.8 Hz), 7.20 (1H, s), 7.30-7.50 (5H, m), 8.65(1H, brs.) 16

(DMSO-d6) 2.30 (3H, s), 5.11 (2H, s), 7.02 (1H, s), 7.16 (1H, s), 7.23(1H, s), 7.33 (1H, t, J = 7.3 Hz), 7.41 (2H, t, J = 7.3 Hz), 7.48 (2H,d, J = 7.3 Hz), 11.67 (1H, s) 17

(CDCl3) 2.39 (3H, s), 5.12 (2H, s), 6.40- 6.50 (1H, m), 7.05-7.15 (2H,m), 7.18 (1H, s), 7.25-7.35 (1H, m), 7.35-7.45 (2H, m), 7.45-7.55 (2H,m), 7.94 (1H, brs.) 18

(DMSO-d6) 2.31 (3H, s), 5.14 (2H, s), 7.31 (1H, s), 7.33 (1H, d, J = 7.3Hz), 7.40 (2H, t, J = 7.3 Hz), 7.51 (2H, d, J = 7.6 Hz), 7.66 (1H, s),8.13 (1H, d, J = 2.9 Hz), 9.87 (1H, s), 11.92 (1H, s) 19

(DMSO-d6) 2.34 (3H, s), 5.15 (2H, s), 7.21 (1H, s), 7.24 (1H, s), 7.34(1H, d, J = 7.4 Hz), 7.40 (2H, t, J = 7.7 Hz), 7.49 (2H, d, J = 7.4 Hz),7.60 (1H, d, J = 2.9), 8.41 (1H, brs.)

TABLE 3 Ref No. Strc (Solv) ¹H-NMR δ ppm: 20

(DMSO-d6) 1.37 (3H, t, J = 7.1 Hz), 4.38 (2H, q, J = 7.1 Hz), 6.95-7.05(1H, m), 7.80- 7.95 (3H, m), 8.06 (1H, dd, J = 8.0 Hz, 2.0 Hz),8.15-8.25 (3H, m), 8.40-8.50 (1H, m) 21

(CDCl3) 6.56 (1H, d, J = 3.7 Hz), 7.40-7.55 (3H, m), 7.80-7.95 (2H, m),8.05 (1H, s), 9.65 (1H, s) 22

(DMSO-d6) 1.36 (3H, t, J = 7.1 Hz), 4.38 (2H, q, J = 7.1 Hz), 6.90-6.95(1H, m), 7.65-7.90 (4H, m), 8.08 (1H, d, J = 3.4 Hz), 8.15-8.30 (3H, m),10.0 (1H, s) 23

(DMSO-d6) 1.30-1.40 (3H, m), 2.03 (3H, s), 4.30-4.45 (2H, m), 5.16 (2H,s), 6.70-6.80 (1H, m), 7.10-7.25 (1H, m), 7.60-7.85 (5H, m), 8.15 (2H,d, J = 8.6 Hz)

TABLE 4 Ex No. Strc (Solv) ¹H-NMR δ ppm: 1

(CDCl3) 1.33 (1H, t, J = 7.1 Hz), 3.44 (3H, s), 4.32 (2H, q, J = 7.1Hz), 5.39 (2H, s), 7.30-7.55 (2H, m), 7.70-7.95 (3H, m), 8.75 (1H, s) 2

(DMSO-d6) 1.37 (3H, t, J = 7.1 Hz), 4.41 (2H, q, J = 7.1 Hz), 7.20-7.35(2H, m), 7.70-8.05 (3H, m), 8.75 (1H, s) 3

(DMSO-d6) 7.15-7.35 (2H, m), 7.75-7.95 (2H, m), 8.00 (1H, d, J = 8.2Hz), 8.75 (1H, s) 4

(CDCl3) 1.42 (3H, t, J = 7.1 Hz), 3.54 (3H, s), 4.42 (2H, q, J = 7.1Hz), 5.07 (2H, s), 5.29 (2H, s), 7.00-7.20 (3H, m), 7.25-7.55 (6H, m),7.70 (1H, d, J = 8.8 Hz), 7.73 (1H, s), 7.97 (1H, d, J = 8.2 Hz) 5

(DMSO-d6) 5.17 (2H, s), 7.11 (1H, dd, J = 8.7 Hz, 2.0 Hz), 7.15-7.55(8H, m), 7.64 (1H, d, J = 8.7 Hz), 7.99 (1H, d, J = 8.4 Hz), 8.52 (1H,s) 6

(DMSO-d6) 1.42 (3H, t, J = 7.2 Hz), 3.45 (3H, s), 4.31 (2H, q, J = 7.2Hz), 5.37 (2H, s), 6.88 (1H, dd, J = 8.7 Hz, 1.7 Hz), 7.05 (1H, d, J =1.7 Hz), 7.34 (1H, dd, J = 8.4 Hz, 1.8 Hz), 7.44 (1H, d, J = 1.8 Hz),7.53 (1H, d, J = 8.4 Hz), 7.86 (1H, d, J = 8.4 Hz), 8.44 (1H, s), 9.68(1H, brs.) 7

(CDCl3) 1.42 (3H, t, J = 7.2 Hz), 3.54 (3H, s), 3.62 (2H, m), 4.04 (2H,t, J = 4.9 Hz), 4.41 (2H, q, J = 7.2 Hz), 5.10 (2H, s), 5.22 (1H, br.s.), 5.31 (2H, s), 6.90-7.10 (2H, m), 7.14 (1H, dd, J = 8.5, 1.9 Hz),7.20-7.40 (6H, m), 7.68 (1H, d ,J = 8.5 Hz), 7.73 (1H, s), 7.99 (1H, d,J = 8.5 Hz)

TABLE 5 Ex No. Strc (Solv) ¹H-NMR δ ppm:  8

(DMSO-d6) 3.30-3.50 (2H, m), 3.95-4.1 (2H, m), 5.01 (2H, s), 6.95-7.55(10H, m), 7.64 (1H, d, J = 8.6 Hz), 8.01 (1H, d, J = 8.5 Hz), 8.53 (1H,s)  9

(DMSO-d6) 3.10-3.50 (2H, m), 4.10-4.30 (2H, m), 7.05-7.35 (4H, m), 7.70(1H, d, J = 8.6 Hz), 7.95-8.25 (3H, m), 8.57 (1H, s) 10

(CDCl3) 1.42 (3H, t, J = 7.1 Hz), 3.10 (2H, t, J = 5.1 Hz), 3.99 (2H, t,J = 5.1 Hz), 4.42 (2H, q, J = 7.1 Hz), 5.32 (2H, s), 7.02 (1H, dd, J =8.7 Hz, 2.2 Hz), 7.05 (1H, d, J = 2.2 Hz), 7.16 (1H, dd, J = 8.3 Hz, 1.9Hz), 7.36 (1H, d, J = 1.9 Hz), 7.69 (1H, d, J = 8.7 Hz), 7.73 (1H, s),7.98 (1H, d, J = 8.3 Hz) 11

(CDCl3) 1.42 (3H, t, J = 7.1 Hz), 2.01 (3H, s), 3.55 (3H, s), 3.60-3.75(2H, m), 3.68 (2H, q, J = 5.8 Hz), 4.03 (2H, t, J = 5.0 Hz), 4.42 (2H,q, J = 7.1 Hz), 5.32 (2H, s), 5.92 (1H, br. s.), 7.00 (1H, dd, J = 8.5,2.2 Hz), 7.03 (1H, d, J = 2.2 Hz), 7.15 (1H, dd, J = 8.3, 2.1 Hz), 7.35(1H, d, J = 2.1 Hz), 7.70 (1H, d, J = 8.5 Hz), 7.74 (1H, s), 7.99 (1H,d, J = 8.3 Hz) 12

(DMSO-d6) 1.81 (3H, s), 3.30-3.50 (2H, m), 3.95-4.10 (2H, m), 6.95-7.35(4H, m), 7.60-7.7 (1H, m), 7.95-8.2 (2H, m), 8.53 (1H, s) 13

(DMSO-d6) 1.36 (3H, t, J = 7.1 Hz), 4.37 (2H, q, J = 7.1 Hz), 7.55 (1H,dd, J = 8.9 Hz, 1.8 Hz), 7.66 (1H, d, J = 8.9 Hz), 7.80-7.90 (2H, m),7.96 (1H, d, J = 1.8 Hz), 8.15-8.25 (2H, m), 8.77 (1H, s)

TABLE 6 Ex No. Strc (Solv) ¹H-NMR δ ppm: 14

(DMSO-d6) 1.35 (3H, t, J = 7.0 Hz), 3.82 (3H, s), 4.37 (2H, q, J = 7.0Hz), 7.05 (2H, d, J = 8.5 Hz), 7.68 (1H, dd, J = 9.3 Hz, 1.6 Hz), 7.71(2H, d, J = 8.5 Hz), 7.76 (1H, d, J-8.5 Hz), 7.87 (2H, d, J = 8.5 Hz),7.92 (1H, d, J = 1.6 Hz), 8.19 (2H, d, J = 8.5 Hz), 8.74 (1H, s) 15

(DMSO-d6) 3.82 (3H, s), 7.05 (2H, d, J = 8.9 Hz), 7.67-7.72 (3H, m),7.75 (1H, d, J = 8.9 Hz), 7.84 (2H, d, J = 8.4 Hz), 7.91 (1H, d, J = 1.5Hz), 8.17 (2H, d, J = 8.9 Hz), 8.73 (1H, s), 13.3 (1H, s-br) 16

(DMSO-d6) 1.26 (3H, t, J = 7.2 Hz), 1.35 (3H, t, J = 7.2 Hz), 4.20 (2H,q, J = 7.2 Hz), 4.37 (2H, q, J = 7.2 Hz), 6.74 (1H, d, J = 16.2 Hz),7.70 (1H, d, J = 8.5 Hz), 7.80-7.90 (4H, m), 8.15-8.25 (3H, m), 8.77(1H, s), 17

(DMSO-d6) 6.61 (1H, d, J = 16.1 Hz), 7.69 (1H, d, J = 8.9 Hz), 7.76-7.82(5H, m), 8.10 (1H, s), 8.16 (2H, d, J = 8.5 Hz), 8.74 (1H, s) 18

(DMSO-d6) 1.36 (3H, t, J = 7.1 Hz), 4.37 (2H, q, J = 7.1 Hz), 5.36 (2H,s), 7.00 (1H, d, J = 7.9 Hz), 7.20-7.50 (5H, m), 7.55-7.65 (2H, m),7.75-7.90 (2H, m), 8.10-8.25 (2H, m), 8.60 (1H, s) 19

(DMSO-d6) 5.37 (2H, s), 6.95-7.10 (1H, m), 7.20-7.5 (5H, m), 7.55-7.70(2H, m), 7.80 (2H, d, J = 8.1 Hz), 8.16 (2H, d, J = 8.1 Hz), 8.61 (1H,s), 13.10-13.40 (1H, brs.) 20

(DMSO-d6) 1.37 (3H, t, J = 7.1 Hz), 4.39 (2H, q, J = 7.1H), 7.90-8.00(2H, m), 8.03 (1H, m), 8.20-8.30 (3H, m), 8.43 (1H, d, J = 2.0 Hz), 9.08(1H, s)

TABLE 7 Ex No. Strc (Solv) ¹H-NMR δ ppm: 21

(DMSO-d6) 1.36 (3H, t, J = 7.1 Hz), 4.37 (2H, q, J = 7.1 Hz), 5.32 (2H,brs.), 6.72 (1H, dd, J = 8.5 Hz, 1.8 Hz), 6.82 (1H, d, J = 1.8 Hz), 7.39(1H, d, J = 8.5 Hz), 7.76 (2H, d, J = 8.6 Hz), 8.16 (2H, d, J = 8.6 Hz),8.29 (1H, s) 22

(DMSO-d6) 1.36 (3H, t, J = 7.1 Hz), 2.97 (3H, s), 4.38 (2H, q, J = 7.1Hz), 7.28 (1H, dd, J = 8.6 Hz, 1.9 Hz), 7.56 (1H, d, J = 1.9 Hz), 7.75(1H, d, J = 8.6 Hz), 7.80-7.90 (2H, m), 8.15-8.25 (2H, m), 9.82 (1H, s)23

(DMSO-d6) 2.97 (3H, s), 7.00-7.85 (5H, m), 8.00-8.25 (2H, m), 9.00-10.0(1H, s), 8.65 (1H, s), 13.0-13.5 (1H, brs.) 24

(CDCl3) 1.44 (3H, t, J = 7.1 Hz), 4.44 (2H, q, J = 7.1 Hz), 5.16 (2H,s), 7.08 (1H, dd, J = 9.1 Hz, 2.5 Hz), 7.30-7.65 (9H, m), 7.79 (1H, s),8.20- 8.3 (2H, m) 25

(DMSO-d6) 1.35 (3H, t, J = 7.1 Hz), 4.37 (2H, q, J = 7.1 Hz), 6.90 (1H,dd, J = 8.9 Hz, 2.3 Hz), 7.01 (1H, d, J = 2.3 Hz), 7.54 (1H, d, J = 8.9Hz), 7.75-7.85 (2H, m), 8.10-8.25 (2H, m), 8.56 (1H, s), 9.55 (1H, brs.)26

(CDCl3) 1.43 (3H, t, J = 7.2 Hz), 4.44 (2H, q, J = 7.2 Hz), 5.32 (2H,s), 6.90-7.40 (6H, m), 7.46 (1H, d, J = 8.9 Hz), 7.56 (2H, d, J = 8.5Hz), 7.79 (1H, s), 8.24 (2H, d, J = 8.5 Hz) 27

(DMSO-d6) 5.42 (2H, s), 6.95-7.45 (4H, m), 7.50-7.85 (4H, m), 8.10-8.20(2H, m), 8.64 (1H, s), 13.2 (1H, s)

TABLE 8 Ex No. Strc (Solv) ¹H-NMR δ ppm: 28

(CDCl3) 1.44 (3H, t, J = 7.2 Hz), 4.45 (2H, q, J = 7.2 Hz), 5.43 (2H,s), 7.30-7.65 (8H, m), 7.91 (1H, s), 8.11 (1H, d, J = 8.8 Hz), 8.28 (2H,d, J = 8.5 Hz), 8.61 (1H, s) 29

(DMSO-d6) 7.65-8.50 (7H, m), 8.82 (1H, s), 13.1 (2H, m) 30

(DMSO-d6) 1.36 (3H, t, J = 7.1 Hz), 4.38 (2H, t, J = 7.1 Hz), 7.75 (1H,d, J = 8.8 Hz), 7.87 (2H, d, J = 8.4 Hz), 7.95-8.05 (1H, m), 8.20 (2H,d, = 8.4 Hz), 8.25-8.35 (1H, m), 8.81 (1H, s) 31

(CDCl3) 1.44 (3H, t, J = 7.2 Hz), 1.77 (1H, t, J = 5.5 Hz), 4.44 (2H, q,J = 7.2 Hz), 4.86 (2H, d, J = 5.5 Hz), 7.41 (1H, dd, J = 8.5, 1.3 Hz),7.50- 7.65 (3H, m), 7.80-7.90 (2H, m), 8.26 (2H, d, J = 8.5 Hz) 32

(DMSO-d6) 4.65(2H, s), 5.20-5.40 (1H, m), 7.30-7.90 (5H, m), 8.00-8.3(2H, m), 8.66 (1H, s), 13.2 (1H, brs.) 33

(DMSO-d6) 1.36 (3 H, t, J = 7.2 Hz), 2.85- 3.15 (6 H, m), 4.38 (2 H, q,J = 7.2 Hz), 7.46 (1 H, dd, J = 8.5, 1.6 Hz), 7.70-7.85 (2 H, m), 7.87(2 H, d, J = 8.8 Hz), 8.20 (2 H, d, J = 8.8 Hz), 8.80 (1 H, s) 34

(DMSO-d6) 3.00 (6H, brs.), 7.45 (1H, dd, J = 8.7 Hz, 1.5 Hz), 7.73 (1H,d, J = 8.7 Hz), 7.75- 7.85 (2H, d, J = 8.5 Hz), 8.77 (1H, s)

TABLE 9 Ex No. Strc (Solv) ¹H-NMR δ ppm: 35

(DMSO-d6) 6.72 (1H, d, J = 3.1 Hz), 6.97 (1H, brs.), 7.40-7.45 (1H, m),7.46-7.52 (1H, m), 7.77 (1H, d, J = 8.1 Hz), 7.84 (1H, d, J = 8.1 Hz),8.69 (1H, s) 36

(DMSO-d6) 1.34 (3H, t, J = 7.1 Hz), 4.37 (2H, q, J = 7.1 Hz), 7.30-7.65(3H, m), 7.70-7.85 (2H, m), 7.90-8.20 (3H, m), 8.69 (1H, s) 37

(DMSO-d6) 7.35-7.50 (2H, m), 7.55-7.65 (1H, m), 7.70-7.85 (2H, m),7.90-8.00 (1H, m), 8.05-8.15 (2H, m), 8.69 (1H, s) 38

(DMSO-d6) 1.38 (3H, t, J = 7.1 Hz), 4.43 (2H, q, J = 7.1 Hz), 7.30-7.55(2H, m), 7.70-7.80 (1H, m), 7.89 (1H, dd, J = 5.1 Hz, 1.3 Hz), 8.25 (1H,s), 8.43 (1H, d, J = 8.5 Hz), 8.80-8.90 (1H, m), 9.10 (1H, s) 39

(DMSO-d6) 7.30-7.95 (4H, m), 8.23 (1H, s), 8.41 (1H, d, J = 8.1 Hz),8.83 (1H, d, J = 5.1 Hz), 9.08 (1H, s), 13.5-14.5 (1H, brs.) 40

(DMSO-d6) 3.91 (3H, s), 7.42 (2H, m), 7.79- 7.80 (2H, m), 8.12-8.19 (2H,m), 8.43 (1H, d, J = 1.9 Hz), 8.75 (1H, s) 41

(DMSO-d6) 7.42-7.46 (2H, m), 7.76 (2H, m), 8.10-8.12 (2H, m), 8.36 (1H,d, J = 1.4 Hz), 8.75 (1H, s) 42

(DMSO-d6) 6.70 (1H, dd, J = 6.5, 2.3 Hz), 7.00 (1H, d, J = 2.0 Hz),7.40-7.47 (2H, m), 7.72 (1H, d, J = 7.8 Hz), 7.76 (1H, d, J = 6.8 Hz),7.95 (1H, d, J = 8.6 Hz), 8.48 (1H, s)

TABLE 10 Ex No. Strc (Solv) ¹H-NMR δ ppm: 43

(DMSO-d6) 2.29 (3H, s), 7.30-7.85 (6H, m), 8.14 (1H, d, 8.0 Hz), 8.69(1H, s) 44

(DMSO-d6) 1.37 (3H, t, J = 7.1 Hz), 4.40 (2H, q, J = 7.1 Hz), 7.40-7.55(2H, m), 7.70-7.80 (1H, m), 8.03 (1H, d, J = 8.8 Hz), 8.45-8.60 (2H, m),9.07 (1H, s), 9.10-9.15 (1H, m) 45

(DMSO-d6) 7.35-7.60 (2H, m), 7.70-7.80 (1H, m), 7.99 (1H, d, J = 8.6Hz), 8.48 (1H, dd, J = 8.6 Hz, 2.3 Hz), 8.53 (1H, d, J = 8.4 Hz), 9.03(1H, s), 9.10-9.15 (1H, m) 46

(DMSO-d6) 1.33 (3H, t, J = 7.1 Hz), 2.71 (3H, s), 4.33 (2H, q, J = 7.1Hz), 7.40-7.65 (2H, m), 7.78 (1H, d, J = 7.9 Hz), 8.50 (1H, d, J = 8.5Hz), 8.97 (1H, s) 47

(DMSO-d6) 2.69 (3H, s), 7.40-7.65 (2H, s), 7.78 (1H, d, J = 8.0 Hz),8.49 (1H, d, J = 8.4 Hz), 8.96 (1H, s), 13.59 (1H, brs.) 48

(DMSO-d6) 1.35 (3H, t, J = 7.3 Hz), 4.38 (2H, q, J = 7.3 Hz), 7.38 (1H,t, J = 7.4 Hz), 7.49 (2H, t, J = 7.6 Hz), 7.72-7.80 (4H, m), 7.88 (2H,d, J = 8.1 Hz), 7.98 (1H, d, J = 1.2 Hz), 8.20 (2H, d, J = 8.1 Hz), 8.75(1H, s), 49

(DMSO-d6) 1.35 (3H, t, J = 7.1 Hz), 4.37 (2H, q, J = 7.1 Hz), 7.38 (1H,t, J = 6.8 Hz), 7.46 (2H, t, J = 7.4 Hz), 7.70-7.73 (3H, m), 7.86 (2H,d, J = 8.2 Hz), 7.92 (2H, d, J = 8.2 Hz), 8.20 (2H, d, J = 8.2 Hz), 8.74(1H, s)

TABLE 11 Ex No. Strc (Solv) ¹H-NMR δ ppm: 50

(DMSO-d6) 3.92 (3H, s), 7.35-7.50 (2H, m), 7.65-7.90 (3H, s), 7.99 (1H,d, J = 2.1 Hz), 8.06 (1H, d, J = 8.4 Hz), 8.73 (1H, s) 51

(DMSO-d6) 2.10 (3H, s), 3.92 (3H, s), 7.14- 7.16 (1H, m), 7.34-7.40 (2H,m), 7.61 (1H, d, J = 8.1 Hz), 7.77-7.79 (1H, m), 7.99 (1H, dd, J = 8.1Hz, 1.8 Hz), 8.11 (1H, d, J = 1.8 Hz), 8.55 (1H, s) 52

(DMSO-d6) 3.94 (3H, s), 7.14-7.42 (3H, m), 7.78 (1H, m), 7.91 (1H, t, J= 8.1 Hz), 8.02- 8.08 (2H, m), 8.65 (1H, s) 53

(DMSO-d6) 3.33 (3H, s), 7.40-7.47 (2H, m), 7.71 (1H, dd, J = 8.5 Hz, 2.0Hz), 7.77-7.79 (2H, m), 7.81 (1H, dd, J = 8.5 Hz, 2.0 Hz), 8.11 (1H, t,J = 8.2 Hz), 8.73 (1H, s) 54

(DMSO-d6) 3.83 (3H, s), 3.93 (3H, s), 7.33 (1H, dd, J = 8.5 Hz, 1.6 Hz).7.39-7.44 (3H, m), 7.76-7.78 (2H, m), 7.88 (1H, d, J = 8.1 Hz), 8.71(1H, s) 55

(DMSO-d6) 1.34 (3H, t, J = 7.1 Hz), 2.33 (3H, s), 4.36 (2H, q, J = 7.1Hz), 5.26 (2H, s), 7.29 (1H, s), 7.34 (1H, t, J = 7.3 Hz), 7.42 (2H, t,J = 7.3 Hz), 7.51 (2H, d, J = 7.3 Hz), 7.55 (1H, s), 7.81 (2H, d, J =8.3 Hz), 8.17 (2H, d, J = 8.3), 8.55 (1H, s), 56

(CDCl3) 1.44 (3H, t, J = 7.1 Hz), 3.48 (3H, s), 3.75-3.85 (2H, m),4.15-4.25 (2H, m), 4.44 (2H, q, J = 7.1 Hz), 7.06 (1H, dd, J = 9.0 Hz,2.4 Hz), 7.24 (1H, d, J = 2.4 Hz), 7.45 (1H, d, J = 9.0 Hz), 7.50-7.65(2H, m), 7.78 (1H, s), 8.20-8.3 (2H, m)

TABLE 12 Ex No. Strc (Solv) ¹H-NMR δ ppm: 57

(CDCl3) 1.44 (3H, t, J = 7.1 Hz), 4.35-4.50 (6H, m), 6.95-7.05 (4H, m),7.25-7.4 (3H, m), 7.46 (1H, d, J = 9.0 Hz), 7.05-7.60 (2H, m), 7.79 (1H,s), 8.20-8.30 (2H, m) 58

(CDCl3) 1.44 (3 H, t, J = 7.1 Hz), 3.85 (3 H, s), 4.44 (2 H, q, J = 7.1Hz), 4.75 (2 H, s), 7.10 (1 H, d, J = 9.1, 2.5 Hz), 7.18 (1 H, d, J =2.5 Hz), 7.48 (1 H, d, J = 9.1 Hz), 7.56 (2 H, d, J = 8.5 Hz), 7.81 (1H, s), 8.25 (2 H, d, J = 8.5 Hz) 59

(CDCl3) 1.44 (3 H, t, J = 7.2 Hz), 2.13 (3 H, s), 4.20-4.55 (6 H, m),7.04 (1 H, dd, J = 9.1, 2.4 Hz), 7.24 (1 H, d, J = 2.4 Hz), 7.47 (1 H,d, J = 9.1 Hz), 7.56 (2 H, d, J = 8.5 Hz), 7.80 (1 H, s), 8.25 (2 H, d,J = 8.5 Hz) 60

(CDCl3) 1.44 (3 H, t, J = 7.0 Hz), 2.08 (3 H, s), 2.15-2.25 (2H, m),4.15 (2 H, t, J = 6.1 Hz), 4.30 (2 H, t, J = 6.1 Hz), 4.44 (2 H, q, J =7.0 Hz), 6.99 (1 H, dd, J = 8.9, 2.4 Hz), 7.15-7.30 (1 H, m), 7.45 (1 H,d, J = 8.9 Hz), 7.56 (2 H, d, J = 8.2 Hz), 7.79 (1 H, s), 8.25 (2 H, d,J = 8.2 Hz) 61

(DMSO-d6) 1.15 (3 H, t, J = 7.0 Hz), 1.36 (3 H, t, J = 7.1 Hz), 3.53 (2H, q, J = 7.0 Hz), 3.60- 3.90 (2 H, m), 4.10-4.30 (2 H, m), 4.37 (2 H,q, J = 7.1 Hz), 6.95-7.15 (1 H, m), 7.23 (1 H, s), 7.50-7.70 (1 H, m),7.70-7.95 (2H, m), 8.05-8.30 (2 H, m), 8.63 (1H, s) 62

(DMSO-d6) 1.36 (3H, t, J = 7. Hz), 3.70- 3.90 (2H, m), 4.20-4.35 (2H,m), 4.37 (2 H, q, J = 7.0 Hz), 4.58 (2 H, s), 7.05 (1H, dd, J = 9.1, 2.3Hz), 7.15-7.45 (6H, m), 7.62 (1H, d, J = 9.1 Hz), 7.82 (2H, d, J = 8.5Hz), 8.17 (2H, d, J = 8.5 Hz), 8.63 (1H, s)

TABLE 13 Ex No. Strc (Solv) ¹H-NMR δ ppm: 63

(DMSO-d6) 1.36 (3H, t, J = 7.1 Hz), 3.30 (3H, s), 3.60-3.70 (2H, m),4.10-4.20 (2H, m), 4.38 (2H, q, J = 7.1 Hz), 7.04 (1H, dd, J = 8.7 Hz,2.0 Hz), 7.16 (1H, d, J = 2.0 Hz), 7.64 (1H, d, J = 8.7 Hz), 7.84 (2H,d, J = 7.8 Hz), 8.17 (2H, d, J = 7.8 Hz), 8.56 (1H, s) 64

(DMSO-d6) 1.34 (3H, t, J = 7.1 Hz), 2.02 (3H, s). 4.20-4.25 (2H, m),4.30-4.40 (4H, m), 7.05 (1H, dd, J = 8.7 Hz, 2.1 Hz), 7.16 (1H, d, J =2.1 Hz), 7.65 (1H, d, J = 8.7 Hz), 7.80-7.90 (2H, m), 8.15-8.20 (2H, m),8.57 (1H, s) 65

(CDCl3) 1.44 (3 H, t, J = 7.1 Hz), 3.08 (3 H, s), 4.44 (2 H, q, J = 7.1Hz), 5.27 (2 H, s), 7.10 (1 H, dd, J = 8.9, 2.3 Hz), 7.29 (1 H, d, J =2.3 Hz), 7.49 (1 H, d, J = 8.9 Hz), 7.56 (2 H, d, J = 8.5 Hz), 7.70 (2H, d, J = 8.0 Hz), 7.81 (1 H, s), 7.99 (2 H, d, J = 8.0 Hz), 8.26 (2 H,d, J = 8.5 Hz) 66

(DMSO-d6) 1.37 (3H, t, J = 7.1 Hz), 3.86 (3H, s), 4.37 (2H, q, J = 7.1Hz), 6.96 (1H, d, J = 7.2 Hz), 7.29-7.43 (3H, m), 7.72-7.79 (2H, m),7.88 (2H, d, J = 8.2 Hz), 8.00 (1H, s), 8.20 (2H, d, J = 7.9 Hz),8.75-8.77 (1H, m) 67

(DMSO-d6) 1.38 (3H, t, J = 7.2 Hz), 3.79 (3H, s), 4.38 (2H, q, J = 7.2Hz), 7.08 (1H, t, J = 7.5 Hz), 7.15 (1H, d, J = 8.8 Hz), 7.37-7.54 (3H,m), 7.73 (1H, d, J = 8.8 Hz), 7.77 (1H, d, J = 1.3 Hz), 7.88 (2H, d, J =8.4 Hz), 8.19 (2H, d, J = 8.4 Hz), 8.74 (1H, s), 68

(DMSO-d6) 1.35 (3H, t, J = 7.0 Hz), 4.37 (2H, q, J = 7.0 Hz), 7.15-7.29(1H, m), 7.57 (1H, d, J = 5.0 Hz), 7.63 (1H, d, J = 3.5 Hz), 7.70-7.75(2H, m), 7.86 (2H, d, J = 8.3 Hz), 7.95-8.00 (1H, m), 8.19 (2H, d, J =8.3 Hz), 8.74 (1H, s),

TABLE 14 Ex No. Strc (Solv) ¹H-NMR δ ppm: 69

(DMSO-d6) 1.37 (3H, t, J = 7.3 Hz), 4.38 (2H, q, J = 7.3 Hz), 7.80-7.95(6H, m), 8.15- 8.25 (3H, m), 8.60-8.70 (2H, m), 8.80 (1H, s) 70

(DMSO-d6) 1.35 (3H, t, J = 7.1 Hz), 2.95 (6H, s), 4.37 (2H, q, J = 7.1Hz), 6.83 (2H, d, J = 8.6 Hz), 7.55-7.75 (3H, m), 7.72 (1H, d, J = 8.8Hz), 7.80-7.90 (3H, m), 8.19 (2H, d, J = 8.2 Hz), 8.70 (1H, s) 71

(DMSO-d6) 1.35 (3H, t, J = 7.1 Hz), 2.63 (3H, s), 4.38 (2H, q, J = 7.1Hz), 7.80-7.85 (2H, m), 7.85-8.00 (4H, m), 8.00-8.15 (3H, m), 8.15-8.25(2H, m), 8.78 (1H, s) 72

(DMSO-d6) 1.35 (3H, t, J = 7.2 Hz), 3.27 (3H, s), 4.38 (2H, q, J = 7.2Hz), 7.80-7.85 (2H, m), 7.88 (2H, d, J = 8.6 Hz), 8.02 (2H, d, J = 8.6Hz), 8.08 (2H, d, J = 8.6 Hz), 8.10-8.15 (1H, m), 8.20 (2H, d, J = 8.6Hz), 8.80 (1H, s) 73

(DMSO-d6) 1.25 (3H, t, J = 7.2 Hz), 1.30- 1.40 (3H, m), 3.88 (2H, q, J =7.2 Hz), 4.38 (2H, q, J = 7.2 Hz), 6.60-6.75 (4H, m), 7.65- 7.75 (4H,m), 7.85-7.95 (3H, m), 8.87 (1H, s) 74

(DMSO-d6) 1.35 (3H, t, J = 7.2 Hz), 4.37 (2H, q, J = 7.2 Hz), 5.18 (2H,s), 7.14 (2H, d, J = 8.3 Hz), 7.35-7.55 (5H, m), 7.65-7.80 (4H, m),7.85-7.95 (3H, m), 8.19 (2H, d, J = 7.7 Hz), 8.74 (1H, s)

TABLE 15 Ex No. Strc (Solv) ¹H-NMR δ ppm: 75

(DMSO-d6) 1.37 (3H, t, J = 7.2 Hz), 4.37(2H, q, J = 7.2 Hz), 6.85-6.90(2H, m), 7.60-7.70 (1H, m), 7.70-7.80 (2H, m), 7.85-7.95 (3H, m), 8.19(2H, d, J = 8.3 Hz), 8.72 (1H, s) 76

(DMSO-d6) 1.35 (3H, t, J = 7.2 Hz), 3.01 (3H, s), 4.37 (2H, q, J = 7.2Hz), 7.30 (2H, d, J = 8.0 Hz), 7.65-7.80 (4H, m), 7.85-7.90 (2H, m),7.95 (1H, d, J = 1.8 Hz), 8.15-8.25 (2H, m), 8.74 (1H, s) 77

(CDCl3) 1.44 (3 H, t, J = 7.0 Hz), 4.45 (2 H, q, J = 7.0 Hz), 4.71 (2 H,d, J = 5.7 Hz), 6.53 (1 H, br. s.), 7.25-7.70 (8 H, m), 7.85- 8.00 (2 H,m) 8.21 (1 H, s), 8.28 (2 H, d, J = 8.5 Hz) 78

(CDCl3) 1.44 (3 H, t, J = 7.2 Hz), 2.80-3.20 (3 H, m), 4.44 (2 H, q, J =7.2 Hz), 4.50- 4.90 (2 H, m), 7.10-7.70 (9 H, m), 7.80- 8.10 (2 H, m),8.27 (2 H, d, J = 8.2 Hz) 79

(CDCl3) 1.44 (3 H, t, J = 7.2 Hz), 3.43 (3 H, s), 3.62 (2 H, t, J = 5.0Hz), 3.65-3.75 (2H, m), 4.45 (2 H, q, J = 7.2 Hz), 6.62 (1 H, br. s.),7.50-7.65(3 H, m), 7.85-7.95 (2 H, m), 8.20-8.25 (1 H, m), 8.28 (2 H, d,J = 8.5 Hz)

TABLE 16 Ex No. Strc (Solv) ¹H-NMR δ ppm: 80

(CDCl3) 1.44 (3 H, t, J = 7.1 Hz), 3.00-3.90 (10 H, m), 4.45 (2 H, q, J= 7.1 Hz), 7.48 (1 H, dd, J = 8.5, 1.6 Hz), 7.50-7.65 (3 H, m),7.80-8.05 (2 H, m), 8.27 (2 H, d, J = 8.5 Hz) 81

(CDCl3) 1.44 (3H, t, J = 7.2 Hz), 3.20-4.15 (8 H, m), 4.45 (2 H, q, J =7.2 Hz), 7.47 (1 H, dd, J = 8 5, 1.6 Hz), 7.50-7.65 (3 H, m), 7.85-7.95(2 H, m), 8.28 (2 H, d, J = 8.8 Hz) 82

(CDCl3) 1.44 (3 H, t, J = 7.1 Hz), 4.44 (2 H, q, J = 7.1 Hz), 5.17 (2 H,s), 7.07 (1 H, dd, J = 9.0, 2.5 Hz), 7.20 (1 H, dd, J = 4.7, 1.3 Hz),7.25-7.45 (3 H, m), 7.46 (1 H, d, J = 9.0 Hz), 7.56 (2 H, d, J = 8.7Hz), 7.79 (1 H, s), 8.25 (2 H, d, J = 8.7 Hz) 83

(CDCl3) 1.44 (3 H, t, J = 7.1 Hz), 1.95-2.10 (2 H, m), 2.28 (6 H, s),2.49 (2 H, t, J = 7.3 Hz), 4.05-4.20 (2 H, m), 4.44 (2 H, q, J = 7.1Hz), 7.00 (1 H. dd, J = 9.1, 2.3 Hz), 7.24 (1 H, d, J = 2.3 Hz), 7.44 (1H, d, J = 9.1 Hz), 7.56 (2 H, d, J = 8.7 Hz), 7.78 (1 H, s), 8.24 (2 H,d, J = 8.7 Hz) 84

(CDCl3) 1.40-1.50 (12 H, m), 1.95-2.10 (2 H, m), 3.30-3.45 (2 H, m),4.05-4.00 (2 H, m), 4.44 (2 H, q, J = 7.2 Hz), 4.77 (1 H, br. s.), 7.00(1 H, dd, J = 8.9, 2.3 Hz), 7.22 (1 H, d, J = 2.3 Hz), 7.45 (1 H, d, J =8.9 Hz), 7.56 (2 H, d, J = 8.5 Hz), 7.79 (1 H, s), 8.25 (2 H, d, J = 8.5Hz) 85

(DMSO-d6) 1.37 (3H, t, J = 7.1 Hz), 4.39 (2H, q, J = 7.1 Hz), 5.36 (2H,s), 7.05 (1H, d, J = 8.0 Hz), 7.25-7.45 (4H, m), 7.50-7.65 (2H, m), 8.02(1H, d, J = 8.6 Hz), 8.1 (1H, d, J = 8.6 Hz), 8.5 (1H, dd, J = 8.6 Hz,2.4 Hz), 8.95 (1H, s), 9.12 (1H, m)

TABLE 17 Ex No. Strc (Solv) ¹H-NMR δ ppm: 86

(DMSO-d6) 1.30-1.45 (3H, m), 2.47 (3H, s), 4.30-4.45 (2H, m), 7.3 (1H,d, J = 8.7 Hz),7.53 (1H, s), 8.00 (1H, d, J = 8.7 Hz), 8.44 (1H, d, J =8.6 Hz), 8.45-8.55 (1H, m), 9.0 (1H, s), 9 05-9.15 (1H, m) 87

(DMSO-d6) 1.36 (3H, t, J = 7.1 Hz), 2.97 (3H, s), 4.37 (2H, q, J = 7.1Hz), 7.20-7.40 (1H, m), 7.59 (1H, d, J = 2.0 Hz), 7.70 (1H, d, J = 9.0Hz), 7.75-7.90 (2H, m), 8.10-8.25 (2H, m), 8.70 (1H, s), 9.79 (1H, brs.)88

(DMSO-d6) 1.35 (3H, t, J = 7.1 Hz), 2.94 (3H, s), 4.37 (2H, q, J = 7.1Hz), 5.19 (2H, s), 7.05-8.25 (7H, m), 8.73 (1H, s) 89

(DMSO-d6) 1.42 (3H, t, J = 7.1 Hz), 3.55 (3H, s), 4.40 (2H, q, J = 7.1Hz), 5.31 (2H, s), 7.19 (1H, dd, J = 8.3 Hz, 2 Hz), 7.25-7.65 (4H, m),7.80-8.05 (3H, m) 90

(DMSO-d6) 2.47 (3H, s), 3.44 (3H, s), 3.86 (3H, s), 5.38 (2H, s),7.20-7.30 (1H, m), 7.35-7.70 (4H, m), 7.90(1H, d, J = 8.4 Hz), 8.62 (1H,s) 91

(DMSO-d6) 2.44 (3H, s), 3.44 (3H, s), 3.86 (3H, s), 5.39 (2H, s),7.20-7.30 (1H, m), 7.39 (1H, dd, J = 8.3 Hz, 2.0 Hz), 7.50 (1H, d, J =2.0 Hz), 7.52 (1H, s), 7.65 (1H, d, J = 8.2 Hz), 7.90 (1H, d, J = 8.4Hz), 8.59 (1H, s) 92

(DMSO-d6) 1.33 (3H, t, J = 7.1 Hz), 3.44 (3H, s), 4.32 (2H, q, J = 7.1Hz), 5.38 (2H, s), 7.20-7.65 (4H, m), 7.73 (1H, dd, J = 9.0 Hz, 4.1 Hz),7.88 (1H, d, J = 8.3 Hz), 8.74 (1H, s)

TABLE 18 Ex No. Strc (Solv) ¹H-NMR δ ppm: 93

(DMSO-d6) 1.33 (3H, t, J = 7.1 Hz), 3.44 (3H, s), 4.32 (2H, q, J = 7.1Hz), 5.39 (2H, s), 7.20-7.65 (4H, m), 7.75-7.85 (1H, m), 7.88 (1H, d, J= 8.4 Hz), 8.7 (1H, s) 94

(DMSO-d6) 1.33 (3H, t, J = 7.1 Hz), 3.44 (3H, s), 4.32 (2H, q, J = 7.1Hz), 5.38 (2H, s), 7.41 (1H, dd, J = 8.3 Hz, 2 Hz), 7.50 (1H, d, J = 2.0Hz), 7.80-7.95 (3H, m), 8.79 (1H, s) 95

(DMSO-d6) 3.43 (3H, s), 3.85 (3H, s), 5.39 (2H, s), 6.10 (2H, s), 7.21(1H, s), 7.23 (1H, s), 7.30-7.50 (2H, m), 7.85-7.95 (1H, m), 8.45 (1H,s) 96

(DMSO-d6) 1.33 (3H, t, J = 7.1 Hz), 3.44 (3H, s), 4.33 (2H, q, J = 7.1Hz), 5.37 (2H, s), 7.40-7.50 (1H, m), 7.55-7.60 (1H, m), 7.65- 7.80 (1H,m), 7.91 (1H, d, J = 8.3 Hz), 7.95- 8.1 (2H, m), 8.92 (1H, s) 97

(DMSO-d6) 1.32 (3H, t, J = 7.1 Hz), 3.44 (3H, s), 3.86 (3H, s), 4.32(2H, q, J = 7.1 Hz), 5.38 (2H, s), 7.03 (1H, dd, J = 9.1 Hz, 2.4 Hz),7.21 (1H, d, J = 2.4 Hz), 7.30-7.55 (2H, m), 7.63 (1H, d, J = 9.1 Hz),7.87 (1H, d, J = 8.2 Hz), 8.62 (1H, s) 98

(DMSO-d6) 1.32 (3H, t, J = 7.1 Hz), 3.44 (3H, s), 4.32 (2H, q, J = 7.1Hz), 5.38 (2H, s), 7.4 (1H, dd, J = 8.3 Hz, 2.1 Hz), 7.44 (1H, dd, J =8.9 Hz, 2.0 Hz), 7.5 (1H, d, J = 2.1 Hz), 7.73 (1H, d, J = 8.9 Hz), 7.83(1H, d, J = 2 Hz), 7.88 (1H, d, J = 8.3 Hz), 8.76 (1H, s)

TABLE 19 Ex No. Strc (Solv) ¹H-NMR δ ppm: 99

(DMSO-d6) 1.32 (3H, t, J = 7.1 Hz), 3.46 (3H, s), 4.32 (2H, q, J = 7.1Hz), 5.40 (2H, s), 7.35-7.55 (5H, m), 7.70-7.85 (4H, m), 7.90 (1H, d, J= 8.3 Hz), 7.98 (1H, s), 8.72 (1H, s) 100

(DMSO-d6) 1.32 (3H, t, J = 7.1 Hz), 3.45 (3H, s), 4.32 (2H, q, J = 7.1Hz), 5.40 (2H, s), 7.35-7.50 (4H, m), 7.62 (1H, d, J = 2.0 Hz),7.70-7.75 (3H, m), 7.85 (1H, d, J = 8.4 Hz), 7.90-7.95 (2H, m), 8.72(1H, s), 101

(DMSO-d6) 1.41 (3H, t, J = 7.2 Hz), 3.55 (3H, s), 4.41 (2H, q, J = 7.2Hz), 5.15 (2H, s), 5.31 (2H, s), 7.08 (1H, dd, J = 9.1 Hz, 2.4 Hz), 7.16(1H, dd, J = 8.3 Hz, 2.0 Hz), 7.30-7.55 (8H, m), 7.78 (1H, s), 7.97 (1H,d, J = 8.3 Hz) 102

(DMSO-d6) 1.34 (3H, t, J = 7.1 Hz), 3.44 (3H, s), 4.31 (2H, q, J = 7.1Hz), 5.30-5.40 (4H, m), 6.99 (1H, d, J = 7.5 Hz), 7.25-7.50 (7H, m),7.59 (2H, d, J = 7.6 Hz), 7.86 (1H, d, J = 8.4 Hz), 8.58 (1H, s) 103

(DMSO-d6) 1.33 (3H, t, J = 7.1 Hz), 3.44 (3H, s), 4.33 (2H, q, J = 7.1Hz), 5.37 (2H, s), 7.41 (1H, dd, J = 8.3 Hz, 2.0 Hz), 7.52 (1H, d, J =2.0 Hz), 7.79 (1H, dd, J = 8.7 Hz, 1.6 Hz), 7.80-7.87 (1H, m), 7.89 (1H,d, J = 8.3 Hz), 8.35-8.4 (1H, m), 8.88 (1H, s) 104

(DMSO-d6) 1.33 (3H, t, J = 7.1 Hz), 3.44 (3H, s), 4.33 (2H, q, J = 7.1Hz), 5.39 (2H, s), 7.40-7.60 (2H, m), 7.70-8.1 (3H, m), 8.24 (1H, s),8.94 (1H, s)

TABLE 20 Ex No. Strc (Solv) ¹H-NMR δ ppm: 105

(DMSO-d6) 1.33 (3H, t, J = 7.1 Hz), 3.44 (3H, s), 4.33 (2H, q, J = 7.1Hz), 5.37 (2H, s), 7.41 (1H, dd, J = 8.3 Hz, 2.0 Hz), 7.50-7.60 (2H, m),7.85-7.95 (2H, m), 8.0-8.05 (1H, m), 8.94 (1H, s) 106

(DMSO-d6) 1.33 (3H, t, J = 7.1 Hz), 3.44 (3H, s), 4.32 (2H, q, J = 7.1Hz), 5.38 (2H, s), 7.15-7.60 (5H, m), 7.88 (1H, d, J = 8.3 Hz), 8.73(1H, s) 107

(DMSO-d6) 1.20-1.35 (9H, m), 3.00-3.10 (1H, m), 3.45 (3H, s), 4.32 (2H,q, J = 7.1 Hz), 5.39 (2H, s), 6.80-7.95 (6H, m), 8.62 (1H, s) 108

(DMSO-d6) 1.32 (3H, t, J = 7.1 Hz), 3.44 (3H, s), 4.31 (2H, q, J = 7.1Hz), 6.89 (1H, dd, J = 9.0 Hz, 2.4 Hz), 7.01 (1H, d, J = 2.4 Hz), 7.36(1H, dd, J = 8.3 Hz, 2.0 Hz), 7.45 (1H, d, J = 2.0 Hz), 7.55 (1H, d, J =9.0 Hz), 7.86 (1H, d, J = 8.3 Hz), 8.53 (1H, s), 9.54 (1H, brs.) 109

(DMSO-d6) 1.32 (3H, t, J = 7.1 Hz), 3.45 (3H, s), 4.32 (2H, q, J = 7.1Hz), 5.38 (2H, s), 6.70 (1H, d, J = 13.0 Hz), 7.07 (1H, d, J = 8.0 Hz),7.23 (1H, t, J = 8.0 Hz), 7.40 (1H, dd, J = 8.3 Hz, 2.0 Hz), 7.52 (1H,d, J = 2.0 Hz), 7.89 (1H, d, J = 8.3 Hz), 8.72 (1H, s), 9.82 (1H, s) 110

(DMSO-d6) 1.09 (6H, d, J = 6.4 Hz), 1.34 (3H, t, J = 7.1 Hz), 2.00-2.20(1H, m), 3.44 (3H, s), 3.95 (2H, d, J = 5.5 Hz), 4.31 (2H, q, J = 7.1Hz), 5.37 (2H, s), 6.83 (1H, d, J = 7.4 Hz), 7.20-7.40 (3H, m), 7.46(1H, s), 7.86 (1H, d, J = 8.2 Hz), 8.53 (1H, s)

TABLE 21 Ex No. Strc (Solv) ¹H-NMR δ ppm: 111

(DMSO-d6) 1.01 (6H, d, J = 6.6 Hz), 1.32 (3H, t, J = 7.1 Hz), 2.00-2.15(1H, m), 3.44 (3H, s), 3.85 (2H, d, J = 6.6 Hz), 4.32 (2H, q, J = 7.1Hz), 5.38 (2H, s), 7.30 (1H, dd, J = 9.1 Hz, 2.4 Hz), 7.19 (1H, d, J =2.4 Hz), 7.37 (1H, dd, J = 8.3 Hz, 2.0 Hz), 7.47 (1H, d, J = 2.0 Hz),7.62 (1H, d, J = 9.1 Hz), 7.87 (1H, d, J = 8.3 Hz), 8.59 (1H, s) 112

(DMSO-d6) 1.25-1.40 (9H, m), 3.44 (3H, s), 4.32 (2H, q, J = 7.1 Hz),4.65-4.80 (1H, m), 5.38 (2H, s), 7.00 (1H, dd, J = 9.0 Hz, 2.3 Hz), 7.19(1H, d, J = 2.3 Hz), 7.37 (1H, dd, J = 8.3 Hz, 2.0 Hz), 7.47 (1H, d, J =2.0 Hz), 7.61 (1H, d, J = 9.0 Hz), 7.87 (1H, d, J = 8.3 Hz), 8.59 (1H,s) 113

(DMSO-d6) 1.32 (3H, t, J = 7.1 Hz), 2.06 (3H, s), 3.44 (3H, s),4.25-4.45 (6H, m), 5.38 (2H, s), 7.05 (1H, dd, J = 9.1 Hz, 2.4 Hz), 7.25(1H, d, J = 2.4 Hz), 7.38 (1H, dd, J = 8.4 Hz, 2.0 Hz), 7.47 (1H, d, J =2.0 Hz), 7.64 (1H, d, J = 9.1 Hz), 7.87 (1H, d, J = 8.4 Hz), 8.61 (1H,s) 114

(DMSO-d6) 1.32 (3H, t, J = 7.1 Hz), 3.33 (3H, s), 3.44 (3H, s), 3.65-3.8(2H, m), 4.15-4.25 (2H, m), 4.32 (2H, q, J = 7.1 Hz), 5.38 (2H, s),6.95-7.10 (1H, m), 7.15-7.25 (1H, m), 7.30-7.5 (2H, m), 7.63 (1H, d, J =9.1 Hz), 7.87 (1H, d, J = 8.2 Hz), 8.60 (1H, s) 115

(CDCl3) 1.41 (3 H, t, J = 7.1 Hz), 3.55 (3 H, s), 3.84 (3 H, s), 4.41 (2H, q, J = 7.1 Hz), 4.74 (2 H, s), 5.30 (2 H, s), 7.05-7.25 (3 H, m),7.33 (1 H, d, J = 1.9 Hz), 7.49 (1 H, d, J = 8.9 Hz), 7.79 (1 H, s),7.97 (1 H, d, J = 8.2 Hz) 116

(CDCl3) 1.41 (3 H, t, J = 7.3 Hz), 1.47 (3 H, t, J = 6 9 Hz), 3.55 (3 H,s), 4.13 (2 H, q, J = 6.9 Hz), 4.41 (2 H, q, J = 7.3 Hz), 5.31 (2 H, s),7.00 (1 H, dd, J = 9.0, 2.5 Hz), 7.16 (1 H, dd, J = 8.4, 2.1 Hz), 7.21(1 H, d, J = 2.5 Hz), 7.34 (1 H, d, J = 2.1 Hz), 7.46 (1 H, d, J = 9.0Hz), 7.77 (1 H, s), 7.97 (1 H, d, J = 8.4 Hz)

TABLE 22 Ex No. Strc (Solv) ¹H-NMR δ ppm: 117

(CDCl3) 1.42 (3 H, t, J = 7.2 Hz), 3.45 (3 H, s), 3.55 (3 H, s),3.70-3.85 (2 H, m), 4.05- 4.20 (2 H, m), 4.41 (2 H, q, J = 7.2 Hz), 5.31(2 H, s), 7.05 (1 H, dd, J = 8.8, 1.9 Hz), 7.08 (1 H, d, J = 1.9 Hz),7.15 (1 H, dd, J = 8.3, 1.8 Hz), 7.35 (1 H, d, J = 1.8 Hz), 7.68 (1 H,d, J = 8.8 Hz), 7.73 (1 H, s), 7.98 (1 H, d, J = 8.3 Hz) 118

(CDCl3) 1.42 (3 H, t, J = 7.1 Hz), 3.56 (3 H, s), 3.80 (3 H, s), 4.42 (2H, q, J = 7.1 Hz), 4.66 (2 H, s), 5.33 (2 H, s), 7.06 (1 H, dd, J = 8.8,2.2 Hz), 7.08 (1 H, d, J = 2.2 Hz), 7.13 (1 H, dd, J = 8.3, 1.8 Hz),7.35 (1 H, d, J = 1.8 Hz), 7.72 (1 H, d, J = 8.8 Hz), 7.75 (1 H, s),7.98 (1 H, d, J = 8.3 Hz) 119

(CDCl3) 1.42 (3 H, t, J = 7.1 Hz), 2.09 (3 H, s), 3.55 (3 H, s), 4.17 (2H, t, J = 4.7 Hz), 4.35-4.50 (4 H, m), 5.32 (2 H, s), 6.95- 7.10 (2 H,m), 7.15 (1 H, dd, J = 8.2, 1.3 Hz), 7.35 (1 H, d, J = 1.3 Hz), 7.70 (1H, d, J = 8.5 Hz), 7.74 (1 H, s), 7.98 (1 H, d, J = 8.2 Hz) 120

(CDCl3) 1.23 (3 H, t, J = 7.0 Hz), 1.42 (3 H, t, J = 7.2 Hz), 3.56 (3H,s), 3.60 (2 H, q, J = 7.0 Hz), 3.75-3.85 (2 H, m), 4.05-4.20 (2 H, m),4.41 (2 H, q, J = 7.2 Hz), 5.31 (2 H, s), 7.04 (1 H, dd, J = 8.8, 2.1Hz), 7.08 (1 H, d, J = 2.1 Hz), 7.15 (1 H, dd, J = 8.3, 2.2 Hz), 7.35 (1H, d, J = 2.2 Hz), 7.68 (1 H, d, J = 8.8 Hz), 7.72 (1 H, s), 7.97 (1 H,d, J = 8.3 Hz) 121

(CDCl3) 1.04 (3 H, t, J = 7.4 Hz), 1.42 (3 H, t, J = 7.0 Hz), 1.70-1.95(2 H, m), 3.55 (3 H, s), 3.91 (2 H, t, J = 6.6 Hz), 4.41 (2 H, q, J =7.0 Hz), 5.31 (2 H, s), 7.01 (1 H, dd, J = 8.5, 1.9 Hz), 7.03 (1 H, d, J= 1.9 Hz), 7.16 (1 H, dd, J = 8.4, 1.8 Hz), 7.37 (1 H, d, J = 1.8 Hz),7.67 (1 H, d, J = 8.5 Hz), 7.71 (1 H, s), 7.98 (1 H, d, J = 8.4 Hz)

TABLE 23 Ex No. Strc (Solv) ¹H-NMR δ ppm: 122

(CDCl3) 0.98 (3 H, t, J = 7.4 Hz), 1.42 (3 H, t, J = 7.1 Hz), 1.45-1.60(2 H, m), 1.70- 1.85 (2 H, m), 3.55 (3 H, s), 3.95 (2 H, t, J = 6.5 Hz),4.41 (2 H, q, J = 7.1 Hz), 5.31 (2 H, s) 6.95-7.10 (2 H, m), 7.16 (1 H,dd, J = 8.1, 1.5 Hz), 7.37 (1 H, d, J = 1.5 Hz), 7.67 (1 H, d, J = 8.8Hz), 7.71 (1 H, s), 7.98 (1 H, d, J = 8.1 Hz) 123

(CDCl3) 1.42 (3 H, t, J = 7.2 Hz), 3.54 (3H, s), 4.25-4.40 (4 H, m),4.41 (2 H, q, J = 7.2 Hz), 5.31 (2 H, s), 6.85-7.05 (3 H, m), 7.06 (1H,dd, J = 8.8, 2.1 Hz), 7.12 (1 H, d, J = 2.1 Hz), 7.15 (1 H, dd, J = 8.4,1.9 Hz), 7.29 (2 H, t, J = 8.0 Hz), 7.37 (1 H, d, J = 1.9 Hz), 7.70 (1H, d, J = 8.8 Hz), 7.74 (1 H, s), 7.98 (1 H, d, J = 8.4 Hz) 124

(DMSO-d6) 1.25-1.40 (6H, m), 3.44 (3H, s), 4.06 (2H, q, J = 7.0 Hz),4.32 (2H, q, J = 7.1 Hz), 5.39 (2H, s), 7.00 (1H, dd, J = 8.8 Hz, 2.1Hz), 7.16 (1H, d, J = 2.1 Hz), 7.39 (1H, dd, J = 8.4 Hz, 2.0 Hz), 7.52(1H, d, J = 2.0 Hz), 7.63 (1H, d, J = 8.8 Hz), 7.88 (1H, d, J = 8.414z),8.53 (1H, s) 125

(DMSO-d6) 1.27 (6H, d, J = 6.0 Hz), 1.33 (3H, t, J = 7.1 Hz), 3.44 (3H,s), 4.32 (2H, q, J = 7.1 Hz), 4.55-4.75 (1H, m), 5.38 (2H, s), 6.95-7.05(1H, m), 7.10-7.20 (1H, m), 7.30- 7.40 (1H, m), 7.45-7.55 (1H, m), 7.62(1H, d, J = 8.8 Hz), 7.89 (1H, d, J = 8.3 Hz), 8.52 (1H, s) 126

(DMSO-d6) 1.31 (3H, t, J = 7.1 Hz), 1.95- 2.10 (5H, m), 3.44 (3H, s),4.05-4.20 (4H, m), 4.31 (2H, q, J = 7.1 Hz), 5.39 (2H, s), 7.01 (1H, dd,J = 8.6 Hz, 2.1 Hz), 7.17 (1H, d, J = 2.1 Hz), 7.38 (1H, dd, J = 8.6 Hz,1.9 Hz), 7.52 (1H, d, J = 1.9 Hz), 7.63 (1H, d, J = 8.6 Hz), 7.87 (1H,d, J = 8.6 Hz), 8.53 (1H, s)

TABLE 24 Ex No. Strc (Solv) ¹H-NMR δ ppm: 127

(DMSO-d6) 1.34 (3H, t, J = 7.2 Hz), 1.60- 1.85 (4H, m), 2.00 (3H, s),3.44 (3H, s), 4.00-4.10 (4H, m), 4.31 (2H, q, J = 7.2 Hz), 5.39 (2H, s),7.00 (1H, dd, J = 8.6 Hz, 1.8 Hz), 7.16 (1H, d, J = 1.8 Hz), 7.38 (1H,dd, J = 8.6 Hz, 1.8 Hz), 7.51 (1H, d, J = 1.8 Hz), 7.62 (1H, d, J = 8.6Hz), 7.87 (1H, d, J = 8.6 Hz), 8.52 (1H, s) 128

(DMSO-d6) 1.34 (3H, t, J = 7.1 Hz), 3.43 (3H, s), 4.31 (2H, q, J = 7.1Hz), 5.21 (2H, s), 5.38 (2H, s), 7.05-7.15 (1H, m), 7.25-7.70 (8H, m),7.87 (1H, d, J = 8.6 Hz), 8.55 (1H, s) 129

(DMSO-d6) 1.31 (3H, t, J = 7.1 Hz), 3.44 (3H, s), 4.32 (2H, q, J = 7.1Hz), 5.18 (2H, s), 5.38 (2H, s), 7.11 (1H, dd, J = 8.6 Hz, 1.8 Hz), 7.28(1H, d, J = 1.8 Hz), 7.33 (1H, dd, J = 8.6 Hz, 1.8 Hz), 7.35-7.45 (3H,m), 7.49 (1H, d, J = 1.8 Hz), 7.50-7.55 (1H, m), 7.66 (1H, d, J = 8.6Hz), 7.87 (1H, d, J = 8.6 Hz), 8.54 (1H, s) 130

(DMSO-d6) 1.32 (3H, t, J = 7.1 Hz), 3.44 (3H, s), 4.32 (2H, q, J = 7.1Hz), 5.15 (2H, s), 5.38 (2H, s), 7.09 (1H, dd, J = 8.7 Hz, 2.2 Hz), 7.28(1H, d, J = 2.2 Hz), 7.35 (1H, dd, J = 8.3 Hz, 1.9 Hz), 7.40-7.50 (5H,m), 7.65 (1H, d, J = 8.7 Hz), 7.87 (1H, d, J = 8.3 Hz), 8.54 (1H, s) 131

(DMSO-d6) 0.25-0.35 (2H, m), 0.50-0.60 (2H, m), 1.10-1.30 (1H, m), 1.31(3H, t, J = 7.1 Hz), 3.44 (3H, s), 3.84 (2H, d, J = 7.6 Hz), 4.31 (2H,q, J = 7.1 Hz), 5.38 (2H, s), 7.01 (1H, dd, J = 8.8 Hz, 1.8 Hz), 7.14(1H, d, J = 1.8 Hz), 7.37 (1H, dd, J = 8.6 Hz, 1.8 Hz), 7.51 (1H, d, J =1.8 Hz), 7.61 (1H, d, J = 8.6 Hz), 7.87 (1H, d, J = 8.6h1z), 8.51 (1H,s)

TABLE 25 Ex No. Strc (Solv) ¹H-NMR δ ppm: 132

(DMSO-d6) 1.31 (3H, t, J = 7.1 Hz), 1.75- 1.95 (4H, m), 2.00-2.15 (2H,m), 2.65-2.80 (1H, m), 3.45 (3H, s), 3.97 (2H, d, J = 6.8 Hz), 4.31 (2H.d, J = 6.8 Hz), 5.40 (2H, s), 7.00 (1H, dd, J = 8.3 Hz, 2.0 Hz), 7.17(1H, d, J = 2.0 Hz), 7.38 (1H, d, J = 8.3 Hz), 7.53 (1H, d, J = 2.0 Hz),7.61 (1H, d, J = 8.6 Hz), 7.87 (1H, d, J = 8.6 Hz), 8.52 (1H, s) 133

(CDCl3) 1.42 (3 H, t, J = 7.1 Hz), 2.34 (6 H, s), 2.74 (2 H, t, J = 5.6Hz), 3.55 (3 H, s), 4.05 (2H, t, J = 5.6 Hz), 4.42 (2 H, q, J = 7.1 Hz),5.32 (2 H, s), 7.00-7.10 (2 H, m), 7.16 (1 H, dd, J = 8.3, 2.0 Hz), 7.36(1 H, d, J = 2.0 Hz), 7.68 (1 H, d, J = 8.7 Hz), 7.72 (1 H, s), 7.98 (1H, d, J = 8.3 Hz) 134

(DMSO-d6) 0.92 (6H, d, J = 6.8 Hz), 1.31 (3H, t, J = 7.0 Hz), 1.62 (2H,q, J = 6.8 Hz), 1.70-1.85 (1H, m), 3.44 (3H, s), 4.01 (2H, t, J = 6.6Hz), 4.31 (2H, q, J = 7.0 Hz), 5.39 (2H, (s, 7.00 (1H, d, J = 8.7 Hz,2.2 Hz), 7.18 (1H, d, J = 2.2 Hz), 7.38 (1H, dd, J = 8.3 Hz, 1.9 Hz),7.53 (1H, d, H = 1.9 Hz), 7.62 (1H, d, J = 8.7 Hz), 7.87 (1H, d, J = 8.3Hz), 8.53 (1H, s) 135

(CDCl3) 1.42 (3 H, t, J = 7.2 Hz), 1.90-2.05 (2 H, m), 2.23 (6 H, s),2.44 (2 H, t, J = 7.3 Hz), 3.55 (3 H, s), 4.01 (2 H, t, J = 6.5 Hz),4.41 (2 H, J = 7.2 Hz 5.31 (2 H, s), 7.00 (1 H, dd, J = 8.8, 2.1 Hz),7.04 (1 H, d, J = 2.1 Hz), 7.15 (1 H, dd, J = 8.4, 2.1 Hz), 7.36 (1 H,d, J = 2.1 Hz), 7.67 (1 H, d, J = 8.8 Hz), 7.71 (1 H, s), 7.98 (1 H, d,J = 8.4 Hz) 136

(DMSO-d6) 1.35-1.50 (12 H, m), 1.90- 2.05 (2 H, m), 3.25-3.40 (2 H, m),3.55 (3 H, s), 4.01 (2 H, t, J = 6.0 Hz), 4.41 (2 H, q, J = 7.2 Hz),4.73 (1 H, br. s.), 5.32 (2H, s), 7.00 (1 H, dd, J = 8.7, 2.1 Hz) 7.04(1 H, d, J = 2.1 Hz) 7.15 (1 H, dd, J = 8.3, 2.0 Hz) 7.36 (1 H, d, J =2.0 Hz) 7.58 (1 H, d, J = 8.7 Hz) 7.72 (1 H, s) 7.98 (1 H, d, J = 8.3Hz)

TABLE 26 Ex No. Strc (Solv) ¹H-NMR δ ppm: 137

(CDCl3) 1.30-1.55 (3H, m), 1.80-2.05 (2H, m), 2.80-3.05 (2H, m), 3.55(3H, s), 3.95-4.15 (2H, m), 4.30-4.50 (2H, m), 5.32 (2H, s), 6.90-7.25(3H, m), 7.30- 7.45 (1H, m), 7.60-7.80 (2H, m), 7.90- 8.10 (1H, m) 138

(CDCl3) 1.42 (3 H, t, J = 7.1 Hz), 3.02 (3H, s), 3.50-3.65 (5 H, m),4.11 (2 H, t, J = 4.9 Hz), 4.42 (2 H, q, J = 7.1 Hz), 4.77 (1 H, br.s.), 5.32 (2 H, s), 6.99 (1 H, dd, J = 8.7, 2.1 Hz), 7.04 (1 H, d, J =2.1 Hz), 7.15 (1 H, dd, J = 8.3, 2.1 Hz), 7.35 (1 H, d, J = 2.1 Hz),7.71 (1 H, d, J = 8.7 Hz), 7.75 (1 H, s), 7.99 (1 H, d, J = 8.3 Hz) 139

(CDCl3) 1.42 (3 H, t, J = 7.2 Hz), 1.98 (3H, s), 2.00-2.10 (2 H, m),3.46 (2 H, q, J = 6.6 Hz), 3.55 (3 H, s), 4.03 (2 H, t, J = 5.8 Hz),4.42 (2 H, q, J = 7.2 Hz), 5.32 (2 H, s), 5.74 (1 H, br. s.), 6.99 (1 H,dd, J = 8.6, 2.0 Hz), 7.03 (1 H, d, J = 2.0 Hz) 7.15 (1 H, dd, J = 8.2,1.9 Hz), 7.36 (1 H, d, J = 1.9 Hz), 7.69 (1 H, d, J = 8.6 Hz), 7.73 (1H, s), 7.99 (1 H, d, J = 8.2 Hz) 140

(CDCl3) 1.42 (3 H, t, J = 7.1 Hz), 2.00-2.15 (2 H, m), 2.96 (3 H, s),3.39 (2 H, q, J = 6.3 Hz), 3.55 (3 H, s), 4.09 (2 H, t, J = 5.8 Hz),4.41 (2 H, q, J = 7.1 Hz), 4.52 (1 H, br. s.), 5.32 (2 H, s), 6.99 (1 H,dd, J = 8.6, 2.1 Hz), 7.04 (1 H, d, J = 2.1 Hz), 7.16 (1 H, dd, J = 8.2,2.1 Hz), 7.36 (1 H, d, J = 2.1 Hz), 7.69 (1 H, d, J = 8.6 Hz), 7.74 (1H, s), 7.99 (1 H, d, J = 8.2 Hz) 141

(DMSO-d6) 5.37 (2H, s), 7.05 (1H, d, J = 7.9 Hz), 7.30-7.50 (5H, m),8.45-8.55 (1H, m), 8.93 (1H, s), 9.05-9.15 (1H, m)

TABLE 27 Ex No. Strc ¹H-NMR δ ppm (DMSO-d6): 142

7.35-7.50 (2H, m), 7.54-8.85 (3H, m), 7.94 (1H, d, J = 2.2 Hz), 8.04(1H, d, J = 8.3 Hz), 8.72 (1H, s), 13.50-14 (1H, brs.) 143

2.47 (3H, s), 7.25-7.35 (1H, m), 7.54 (1H, s), 8.45 (1H, d, J = 8.6 Hz),8.48 (1H, dd, J = 8.6 Hz, 2.2 Hz), 9.01 (1H, s), 9.09 (1H, d, J = 2.2Hz), 13.00-14.00 (1H, brs.) 144

3.33 (3H, s), 7.10-8.15 (8H, m), 13.30 (1H, brs.) 145

7.35-7.45 (3H, m), 7.75-8.05 (4H, m), 8.55- 8.65 (1H, m), 13.62 (1H,brs.) 146

7.40-746 (2H, m), 7.66-7.67 (1H, m), 7.76- 7.78 (3H, m), 8.10 (1H, t, J= 8.2 Hz), 8.72 (1H, s) 147

2.47 (3H, s), 3.44 (3H, s), 5.37 (2H, s), 7.20- 7.45 (3H, m), 7.56 (1H,m), 7.60-7.65 (1H, m), 7.88 (1H, d, J = 8.3 Hz) 148

3.92 (3H, s), 7.25-7.50 (4H, m), 7.70-7.90 (3H, m), 8.70 (1H, s), 12.4(1H, s-br) 149

2.33 (3H, s), 5.26 (2H, s), 7.25-7.60 (7H, m), 7.70-7.85 (2H, m),8.10-8.25 (2H, m), 8.54 (1H, s), 13.25 (1H, brs.)

TABLE 28 Ex No. Strc ¹H-NMR δ ppm (DMSO-d6): 150

7.30-7.95 (10H, m), 8.10-8.25 (2H, m), 8.74 (1H, s), 13.27 (1H, brs.)151

5.23 (2H, s), 7.11 (1H, dd, J = 9.1 Hz, 2.4 Hz), 7.25-7.55 (5H, m), 7.63(1H, d, 9.1 Hz), 7.75- 7.90 (2H, m), 8.10-8.2 (2H, m), 8.63 (1H, s), 152

6.85-7.10 (2H, m), 7.45-7.90 (3H, m), 8.10- 8.25 (2H, m), 8.55 (1H, s),9.45-9.70 (1H, brs.) 153

3.65-3.75 (2H, m), 4.15-4.25 (2H, m), 7.04 (1H, dd, J = 9.1 Hz, 2.4 Hz),7.22(1H, d, J = 2.3 Hz), 7.62 (1H, d, J = 9.1 Hz), 7.75-7.85 (2H, m),8.10-8.20 (2H, m), 8.64 (1H, s), 13.00-13.50 (1H, brs.) 154

4.30-4.55 (4H, m), 6.90-7.05 (3H, m), 7.07 (1H, dd, J = 9.1 Hz, 2.4 Hz),7.25-7.40 (3H, m), 7.63 (1H, d, J = 9.1 Hz), 7.75-7.85 (2H, m),8.10-8.20 (2H, m), 8.65 (1H, s), 13.10-13.40 (1H, brs.) 155

7.30-7.95 (10H, m), 8.10-8.25 (2H, m), 8.74 (1H, s), 13.32 (1H, brs.)156

3.86 (3H, s), 6.85-8.25 (11H, m), 8.74 (1H, s)

TABLE 29 Ex No. Strc ¹H-NMR δ ppm (DMSO-d6): 157

3.79 (3H, s), 6.90-7.90 (9H, m), 8.10-8.25 (2H, m), 8.73 (1H, s) 158

7.10-7.25 (1H, m), 7.50-8.25 (9H, m), 8.73 (1H, s), 13.24 (1H, brs.) 159

7.75-8.45 (10H, m), 8.75-8.90 (3H, m), 13.34 (1H, brs.) 160

4.45-4.6 (2H, m), 7.70-7.5 (5H, m), 7.65-8.05 (4H, m), 8.10-8.25 (2H,m), 8.35-8.5 (1H, m), 8.79 (1H, s), 9.15-9.3 (1H, m), 13.3 (1H, brs.)161

2.91 (3H, brs.), 4.40-4.85 (2H, m), 7.00-7.6 (6H, m), 7.65-8.0 (4H, m),8.05-8.3 (2H, m), 8.78 (1H, brs.), 13.2 (1H, brs.) 162

3.40-3.6 (4H, m), 7.70-8.0 (4H, m), 8.10-8.25 (2H, m), 8.30-8.45 (1H,m), 8.65-8.85 (2H, m), 13.3 (1H, brs.) 163

3.00 (3H, s), 7.40-8.00 (5H, m), 8.17 (2H, d, J = 8.4 Hz), 8.77 (1H, s),13.2 (1H, brs.)

TABLE 30 Ex No. Strc ¹H-NMR δ ppm (DMSO-d6): 164

3.00-4.0 (8H, m), 7.40-7.55 (1H, m), 7.60-8.0 (4H, m), 8.05-8.30 (2H,m), 8.70-8.85 (1H, m), 13.3 (1H, brs.) 165

2.96 (6H, s), 6.83 (2H, d, J = 8.1 Hz), 7.6 (2H, d, J = 8.1 Hz), 7.65(1H, d, J = 8.1 Hz), 7.73 (1H, d, J = 8.1 Hz), 7.80-7.85 (3H, m), 8.17(2H, d, J = 8.1 Hz), 8.70 (1H, s), 13.2 (1H, s-br) 166

2.63 (3H, s), 7.80-7.90 (4H, m), 7.95 (2H, d, J = 8.5 Hz), 8.06 (2H, d,J = 8.5 Hz), 8.11 (1H, s), 8.18 (2H, d, J = 8.5 Hz), 8.78 (1H, s) 167

3.28 (3H, s), 7.80-7.85 (4H, m), 8.02 (2H, d, J = 8.5 Hz), 8.08 (2H, d,J = 8.5 Hz), 8.13 (1H, s), 8.17 (2H, d, J = 8.7 Hz), 8.79 (1H, s) 168

1.23 (3H, t, J = 7.6 Hz), 2.66 (2H, q, 7.6 Hz), 7.25-7.40 (2H, m),7.65-8.25 (9H, m), 8.73 (1H, s), 13.29 (1H, brs.) 169

1.36 (3H, t, J = 6.5 Hz), 4.08 (2H, q, J = 6.5 Hz), 7.05-7.85 (8H, m),7.90-8.70 (4H, m), 13.2 (1H, brs.) 170

4.77 (2H, s), 6.95-7.25 (2H, m), 7.50-7.90 (3H, m), 8.00-8.25 (2H, m)8.63 (1H, brs.), 12.50-14.0 (2H, m)

TABLE 31 Ex No. Strc ¹H-NMR δ ppm (DMSO-d6): 171

3.70-3.8 (2H, m), 4.09 (2H, t, J = 4.9 Hz), 4.80- 4.95 (1H, m), 7.04(1H, dd, J = 9.1 Hz, 2.5 Hz), 7.21 (1H, d, J = 2.5 Hz), 7.61 (1H, d, J =9.1 Hz), 7.78 (2H, d, J = 8.3 Hz), 8.15 (2H, d, J = 8.3 Hz), 8.62 (1H,s), 13.2 (1H, brs.) 172

1.80-2.00 (2H, m), 3.50-3.70 (2H, m), 4.00- 4.25 (2H, m), 4.40-4.7 (1H,m), 6.95-7.10 (1H, m), 7.15-7.25 (1H, m), 7.50-7.65 (1H, m), 7.70-7.85(2H, m), 8.05-8.25 (2H, m), 8.61 (1H, s), 13.30 (1H, brs.) 173

5.18 (2H, s), 7.00-7.95 (14H, m), 8.10-8.25 (2H, m), 8.71 (1H, s) 174

1.05-1.25 (3H, m), 3.45-3.85 (4H, m), 4.10- 4.25 (2H, m), 6.95-7.35 (2H,m), 7.50-7.95 (3H, m), 8.00-8.30 (2H, m), 8.50-8.75 (1H, m), 13.2 (1H,brs.) 175

3.70-3.95 (2H, m), 4.15-4.40 (2H, m), 4.58 (2H, s), 6.95-7.45 (7H, m),7.50-7.90 (3H, m), 8.05-8.25 (2H, m), 8.62 (1H, s), 13.2 (1H, brs.) 176

5.21 (2H, s), 7.09 (1H, dd, J = 8.8 Hz, 1.6 Hz), 7.22 (1H, d, J = 4.8Hz), 7.32 (1H, d, J = 1.6 Hz), 7.50-7.70 (5H, m), 7.79 (1H, d, J = 8.2Hz), 8.15 (1H, d, J = 8.2 Hz), 8.64 (1H, s), 13.2 (1H, brs.) 177

2.10-2.25 (2H, m), 2.81 (6H, s), 3.15-3.40 (2H, m), 4.17 (2H, t, J = 6.1Hz), 7.04 (1H, dd, J = 9.1 Hz, 2.4 Hz), 7.24 (1H, d, J = 2.4 Hz), 7.64(1H, d, J = 9.1 Hz), 7.75-7.85 (2H, m), 8.10-8.20 (2H, m), 8.65 (1H, s),9.88 (1H, brs.), 13.2 (1H, brs.)

TABLE 32 Ex No. Strc ¹H-NMR δ ppm (DMSO-d6): 178

3.23 (3H, s), 5.38 (2H, s), 7.00-7.45 (2H, m), 7.50-7.45 (2H, m),7.50-8.40 (9H, m), 8.65 (1H, s), 13.20 (1H, brs.) 179

7.00-7.15 (1H, m), 7.55-8.00 (7H, m), 8.10- 8.25 (2H, m), 8.73 (1H, s),10.32 (1H, s), 13.29 (1H, brs.) 180

1.38 (9H, s), 1.80-1.95 (2H, m), 3.05-3.20 (2H, m), 4.00-4.15 (2H, m),6.85-7.10 (2H, m), 7.15-7.25 (1H, m), 7.61 (1H, d, J = 9.2 Hz), 7.79(2H, d, J = 8.0 Hz), 8.15 (2H, d, J = 8.0 Hz), 8.62 (1H, s), 13.2 (1H,brs.) 181

1.95-2.15 (2H, m), 2.90-3.10 (2H, m), 4.10- 4.25 (2H, m), 6.95-7.10 (1H,m) 7.15-7.30 (1H, m), 7.63 (1H, d, J = 9.2 Hz), 7.79 (2H, d, J = 8.0Hz), 7.84 (2H, brs.), 8.16 (2H, d, J = 8.0 Hz), 8.64 (1H, s), 13.2 (1H,brs.) 182

2.98 (3H, s), 7.03 (1H, dd, J = 9.0 Hz, 1.9 Hz), 7.59 (1H, d, J = 1.9Hz), 7.70 (1H, d, J = 9.0 Hz), 7.75-7.85 (2H, m), 8.10-8.20 (2H, m),8.69 (1H, s), 9.78 (1H, s), 13.0-13.5 (1H, brs.) 183

3.03 (3H, s), 7.32 (2H, d, J = 8.1 Hz), 7.69 (1H, dd, J = 7.3, 1.5 Hz),7.75 (2H, d, J = 8.1 Hz), 7.78 (1H, s), 7.83 (2H, d, J = 8.5 Hz), 7.95(1H, d, J = 2.0 Hz), 8.17 (2H, d, J = 8.9 Hz), 8.72 (1H, s) 13.2 (1H,s-br) 184

4.62 (2H, d, J = 5.3 Hz), 5.26 (1H, t, J = 5.3 Hz), 7.25-7.85 (5H, m),8.10-8.25 (2H, m), 8.64 (1H, s), 13.25 (1H, brs.)

TABLE 33 Ex No. Strc ¹H-NMR δ ppm (DMSO-d6): 185

3.30 (3H, s), 3.60-3.70 (2H, m), 4.10-4.20 (2H, m), 7.03 (1H, dd, J =8.7, 1.7 Hz), 7.15 (1H, d, J = 1.7 Hz), 7.64 (1H, d, J = 8.7 Hz), 7.80(2H, d, J = 8.7 Hz), 8.15 (2H, d, J = 8.7 Hz), 8.55 (1H, s) 186

3.65-3.80 (2H, m), 4.03 (2H, t, J = 5.0 Hz), 4.80- 4.95 (1H, m),6.95-7.20 (2H, m), 7.60-7.90 (3H, m), 8.10-8.25 (2H, m), 8.55 (1H, s),13.28 (1H, brs.) 187

2.47 (3H, s), 2.68 (3H, s), 7.30-7.45 (2H, m), 7.55 (1H, s), 8.33 (1H,d, J = 8.6 Hz), 8.89 (1H, s), 13.62 (1H, brs.) 188

7.20-7.50 (4H m), 7.70-7.80 (2H, m), 8.01 (1H, d, J = 8.5 Hz), 8.69 (1H,s) 189

2.46 (3H, S), 7.15-7.35 (3H, m), 7.55 (1H, s), 7.63 (1H, d, J = 8.4 Hz),7.90-8.10 (1H, m), 8.55-8.70 (1H, m) 190

7.15-7.50 (3H, m), 7.35-7.50 (1H, m), 7.65- 7.85 (2H, m), 8.01 (1H, d, J= 8.3 Hz), 8.72 (1H, s) 191

7.15-7.35 (3H, m), 7.58 (1H, dd, J = 8.8 Hz, 2.5 Hz), 7.74 (1H, dd, J =8.8 Hz, 4.4 Hz), 8.01 (1H, d, J = 8.4 Hz), 8.74 (1H, s)

TABLE 34 Ex No. Strc ¹H-NMR δ ppm (DMSO-d6): 192

7.20-7.35 (3H, m), 7.54 (1H, dd, J = 9.9 Hz, 2.2 Hz), 7.79 (1H, dd, J =8.8 Hz, 5.2 Hz), 8.01 (1H, d, J = 8.7 Hz), 8.70 (1H, s) 193

7.20-7.35 (2H, m), 7.86 (1H, d, J = 9.1 Hz), 7.90 (1H, d, J = 9.1 Hz),8.01 (1H, d, J = 8.7 Hz), 8.79 (1H, s) 194

6.10 (2H, s), 7.15-7.25 (4H, m), 7.90-8.05 (1H, m), 8.45 (1H, s) 195

7.10-7.35 (2H, m), 7.65-7.75 (1H, m), 7.92 (1H, s), 7.95-8.10 (2H, m),8.89 (1H, s) 196

3.86 (3H, s), 7.03 (1H, dd, J = 9.0 Hz, 2.5 Hz), 7.15-7.30 (3H, m), 7.64(1H, d, J = 9.0 Hz), 8.00 (1H, d, J = 8.3 Hz), 8.60 (1H, s) 197

7.15-7.35 (3H, m), 7.44 (1H, dd, J = 9.0 Hz, 2.2 Hz), 7.73 (1H, d, J =9.0 Hz), 7.81 (1H, d, J = 2.2 Hz), 8.01 (1H, d, J = 8.4 Hz), 8.75 (1H,s) 198

7.25-7.40 (3H, m), 7.50 (2H, t, J = 7.6 Hz), 7.70- 7.85 (4H, m), 7.97(1H, s), 8.01 (1H, d, J = 9.8 Hz), 8.73 (1H, s)

TABLE 35 Ex No. Strc ¹H-NMR δ ppm (DMSO-d6): 199

7.25-7.55 (5H, m), 7.65-8.05 (6H, m), 8.72 (1H, s) 200

5.22 (2H, s), 7.00-7.60 (9H, m), 7.63 (1H, d, J = 9.0 Hz), 7.96 (1H, 8.4Hz), 8.59 (1H, s) 201

6.90 (1H, dd, J = 9.0 Hz, 2.3 Hz), 7.00 (1H, d, J = 2.1 Hz), 7.15-7.30(2H, m), 7.56 (1H, d, 9.0 Hz), 7.98 (1H, d, J = 8.5 Hz), 8.55 (1H, s),9.58 (1H, brs) 202

5.35 (2H, s), 6.70-6.85 (2H, m), 6.94 (1H, d, J = 8.3 Hz), 7.20 (1H, d,J = 8.8 Hz), 7.26-7.34 (2H, m), 7.35-7.45 (2H, m), 7.59 (2H, d, J = 8.3Hz), 7.81 (1H, d, J = 7.9 Hz), 8.47 (1H, s) 203

6.69 (1H, d, J = 7.6 Hz), 7.11 (1H, d, J = 8.8 Hz), 7.15-7.25 (3H, m),7.98 (1H, d, J = 8.8 Hz), 8.49 (1H, s), 10.3 (1H, s) 204

1.09 (6H, d, J = 6.3 Hz), 2.10-2.15 (1H, m), 3.90 (2H, d, J = 5.8 Hz),6.83 (1H, d, J = 8.1 Hz), 7.19- 7.29 (4H, m), 7.98 (1H, d, J = 8.5 Hz),8.53 (1H, s) 205

1.01 (6H, d, J = 6.6 Hz), 2.00-2.15 (1H, m), 3.85 (2H, d, J = 6.4 Hz),7.03 (1H, dd, J = 9.1 Hz, 2.4 Hz), 7.15-7.30 (3H, m), 7.63 (1H, d, J =9.1 Hz), 7.99 (1H, d, J = 8.3 Hz), 8.59 (1H, s)

TABLE 36 Ex No. Strc ¹H-NMR δ ppm (DMSO-d6): 206

7.20-7.35 (2H, m), 7.75-7.90 (2H, m), 8.02 (1H, d, J = 8.4 Hz), 8.36(1H, s), 8.88 (1H, s) 207

7.25-7.40 (2H, m), 7.70-7.80 (1H, m), 7.96 (1H, d, J = 8.3 Hz), 8.02(1H, d, J = 8.3 Hz), 8.25 (1H, s), 8.94 (1H, s) 208

7.25 (1H, dd, J = 8.5 Hz, 2.1 Hz), 7.31 (1H, d, J = 2.1 Hz), 7.50-7.60(1H, m), 7.85-8.00 (1H, m), 7.95-8.10 (2H, m), 8.94 (1H, s) 209

1.30 (6H, d, J = 6.0 Hz), 4.65-4.80 (1H, m), 7.00 (1H, dd, J = 9.1 Hz,2.3 Hz), 7.10-7.30 (3H, m), 7.61 (1H, d, J = 9.1 Hz), 7.99 (1H, d, J =8.2 Hz), 8.59 (1H, s) 210

3.75 (2H, t, J = 4.8 Hz), 4.09 (2H, d, J = 4.8 Hz), 4.50-5.25 (1H, br.),7.04 (1H, dd, J = 9.1 Hz, 2.2 Hz), 7.15-7.30 (3H, m), 7.63 (1H, d, J =9.1 Hz), 7.99 (1H, d, J = 8.2 Hz), 8.60 (1H, s) 211

3.34 (3H, s), 3.65-3.75 (2H, m), 4.15-4.25 (2H, m), 7.04 (1H, dd, J =9.2 Hz, 2.5 Hz), 7.15- 7.30 (3H, m), 7.63 (1H, d, J = 9.2 Hz), 7.99 (1H,d, J = 8.2 Hz), 8.60 (1H, s) 212

6.87 (1H, dd, J = 6.8, 2.1 Hz), 7.05 (1H, d, J = 2.1 Hz), 7.18-7.21 (2H,m), 7.52 (1H, d, J = 8.4 Hz), 7.98 (1H, d, J = 8.1 Hz), 8.44 (1H, s),9.67 (1H, s)

TABLE 37 Ex No. Strc ¹H-NMR δ ppm (DMSO-d6): 213

4.80 (2H, s), 6.90-7.45 (4H, m), 7.50-7.75 (1H, m), 7.80-8.10 (1H, m),8.62 (1H, s), 13.0 (1H, brs.) 214

1.20-1.55 (3H, m), 4.00-4.25 (2H, m), 6.80- 7.40 (4H, m), 7.50-7.70 (1H,m), 7.80-8.10 (1H, m), 8.40-8.70 (1H, m) 215

3.30 (3H, s), 3.60-3.75 (2H, m), 4.00-4.25 (2H, m), 6.90-7.4 (4H, m),7.50-7.7 (1H, m), 7.90-8.10 (1H, m), 8.52 (1H, s) 216

4.75 (2H, s), 6.95-7.40 (4H, m), 7.65 (1H, d, J = 8.3 Hz), 7.90-8.05(1H, m), 8.54 (1H, s), 13.0 (1H, brs.) 217

3.81 (3H, s), 7.03 (1H, dd, J = 8.8 Hz, 2.1 Hz), 7.05-7.35 (3H, m), 7.64(1H, d, J = 8.8 Hz), 8.01 (1H, d, J = 8.9 Hz), 8.52 (1H, s) 218

3.65-3.80 (2H, m), 3.95-4.15 (2H, m), 6.95- 7.40 (4H, m), 7.63 (1H, d, J= 8.2 Hz), 7.90-8.10 (1H, m), 8.52 (1H, s)

TABLE 38 Ex No. Strc ¹H-NMR δ ppm (DMSO-d6): 219

1.11 (3H, t, J = 7.0 Hz), 3.5 (2H, q, J = 7.0 Hz), 3.60-3.8 (2H, m),4.05-4.20 (2H, m), 6.95-7.35 (4H, m), 7.63 (1H, d, J = 8.7 Hz),7.90-8.10 (1H, m), 8.52 (1H, s) 220

0.98 (3H, t, J = 7.3 Hz), 1.65-1.85 (2H, m), 3.96 (2H, t, J = 6.5 Hz),7.03 (1H, dd, J = 8.7 Hz, 2.0 Hz), 7.10-7.15 (1H, m), 7.20-7.35 (2H, m),7.62 (1H, d, J = 8.7 Hz), 7.90-8.10 (1H, m), 8.51 (1H, s) 221

0.93 (3H, t, J = 7.4 Hz), 1.35-1.55 (2H, m), 1.60- 1.8 (2H, m), 4.0 (2H,t, J = 6.4 Hz), 7.02 (1H, dd, J = 8.8 Hz, 2.0 Hz), 7.13 (1H, d, J = 2.0Hz), 7.15-7.30 (2H, m), 7.62 (1H, d, J = 8.8 Hz), 7.95-8.05 (1H, m),8.51 (1H, s) 222

4.25-4.45 (4H, m), 6.80-7.05 (3H, m), 7.08 (1H, dd, J = 8.8 Hz, 2.0 Hz),7.15-7.45 (5H, m), 7.65 (1H, d, J = 8.8 Hz), 8.0 (1H, d, J = 9.1 Hz),8.53 (1H, s) 223

1.34 (3H, t, J = 7.0 Hz), 4.06 (2H, q, J = 7.0 Hz), 7.02 (1H, dd, J =8.7 Hz, 2.1 Hz), 7.13 (1H, d, J = 2.1 Hz), 7.20-7.30 (2H, m), 7.62 (1H,d, J = 8.7 Hz), 8.00 (1H, d, J = 9.0 Hz), 8.51 (1H, s) 224

1.30 (6H, d, J = 6.0 Hz), 4.55-4.70 (1H, m), 7.02 (1H, dd, J = 8.7 Hz,2.1 Hz), 7.12 (1H, d, J = 2.1 Hz), 7.20-7.30 (2H, m), 7.62 (1H, d, J =8.7 Hz), 7.95-8.05 (1H, m), 8.51 (1H, s),

TABLE 39 Ex No. Strc ¹H-NMR δ ppm (DMSO-d6): 225

7.10-7.5 (4H, m), 7.54 (1H, d, J = 8.4 Hz), 8.01 (1H, d, J = 8.4 Hz),8.74 (1H, s) 226

2.05-2.20 (2H, m), 2.79 (3H, s), 2.80 (3H, s), 3.00-3.5 (2H, m), 4.10(2H, t, J = 6.0 Hz), 7.05 (1H, dd, J = 8.7 Hz, 2.0 Hz), 7.16 (1H, d, J =2.0 Hz), 7.20-7.30 (2H, m), 7.67 (1H, d, J = 8.7 Hz), 8.0 (1H, d, J =8.3 Hz), 8.53 (1H, s), 9.67 (1H, brs.) 227

2.00-2.10 (2H, m), 2.90-3.05 (2H, m), 4.12 (2H, t, J = 6.1 Hz), 7.06(1H, dd, J = 8.7 Hz, 2.1 Hz), 7.17 (1H, d, J = 2.1 Hz), 7.20-7.30 (2H,m), 7.66 (1H, d, J = 8.7 Hz), 7.90-8.10 (4H, m), 8.54 (1H, s) 228

1.85-1.88 (2H, m), 3.54-3.57 (2H, m), 4.05- 4.08 (2H, m), 7.02 (1H, dd,J = 6.2. 1.9 Hz), 7.14 (1H, s), 7.23-7.25 (2H, m), 7.62 (1H, d, J = 8.6Hz), 8.00 (1H, d, J = 8.6 Hz), 8.51 (1H, s) 229

1.55-1.58 (2H, m), 1.74-1.75 (2H, m), 3.43- 3.46 (2H, m), 4.01-4.02 (2H,m), 7.01 (1H, d, J = 8.9 Hz), 7.13 (1H, s), 7.25-7.27 (2H, m), 7.61 (1H,d, J = 8.9 Hz), 7.99 (1H, d, J = 8.6 Hz), 8.51 (1H, s) 230

5.23 (2H, s), 7.11 (1H, dd, J = 6.2, 2.3 Hz), 7.21-7.23 (2H, m), 7.27(1H, d, J = 2.1 Hz), 7.38-7.40 (2H, m), 7.51-7.52 (1H, m), 7.61- 7.63(1H, m), 7.66 (1H, d, J = 8.4 Hz), 7.99 (1H, d, J = 8.1 Hz), 8.55 (1H,s)

TABLE 40 Ex No. Strc ¹H-NMR δ ppm (DMSO-d6): 231

5.19 (2H, s), 7.11 (1H, dd, J = 6.6, 2.2 Hz), 7.17 (1H, dd, J = 6.1, 2.1Hz), 7.22 (1H, d, J = 1.9 Hz), 7.25 (1H, d, J = 1.9 Hz), 7.39-7.44 (3H,m), 7.54 (1H, s), 7.65 (1H, d, J = 8.7 Hz), 7.99 (1H, d, J = 8.7 Hz),8.54 (1H, s) 232

5.17 (2H, s), 7.01 (1H, dd, J = 6.7, 2.1 Hz), 7.19-7.22 (2H, m), 7.25(1H, d, J = 2.1 Hz), 7.45-7.51 (m, 4H), 7.64 (1H, d, J = 8.8 Hz), 7.99(1H, d, J = 8.3 Hz), 8.54 (1H, s) 233

0.32-0.33 (2H, m), 0.56-0.57 (2H, m), 1.19- 1.26 (1H, m), 3.85 (2H, d, J= 6.3 Hz), 7.02 (1H, dd, J = 6.6, 2.1 Hz), 7.11 (1H, d, J = 1.9 Hz),7.23-7.25 (2H, m), 7.61 (1H, d, J = 8.7 Hz), 7.99 (1H, d, J = 8.9 Hz),8.51 (1H, s) 234

1.83-1.90 (4H, m), 2.05-2.07 (2H, m), 2.69- 2.75 (1H, m), 3.98 (2H, d, J= 6.2 Hz), 7.01 (1H, dd, J = 6.5, 2.2 Hz), 7.12 (1H, d, J = 2.2 Hz),7.21-7.22 (2H, m), 7.61 (1H, d, J = 8.7 Hz), 7.99 (1H, d, J = 9.0 Hz),8.51 (1H, s) 235

2.75-2.95 (6H, m), 3.40-3.60 (2H, m), 4.30- 4.45 (2H, m), 7.05-7.35 (4H,m), 7.7 (1H, d, J = 8.7 Hz), 8.01 (1H, d, J = 8.3 Hz), 8.58 (1H, s),9.86 (1H, brs.) 236

0.92 (6H, d, J = 6.6 Hz), 1.55-1.70 (2H, m), 1.75-1.81 (1H, m), 4.03(2H, t, J = 6.6 Hz), 7.02(1H, dd, J = 6.4, 2.0 Hz), 7.14 (1H, d, J = 2.0Hz), 7.23-7.25 (2H, m), 7.61 (1H, d, J = 8.8 Hz), 7.99 (1H, d, J = 8.8Hz), 8.51 (1H, s) 237

1.24 (6H, d, J = 7.2 Hz), 3.02-3.07 (1H, m), 7.22-7.24 (2H, m), 7.31(1H, d, J = 8.3 Hz), 7.52 (1H, s), 7.67 (1H, d, J = 7.6 Hz), 8.00 (1H,d, J = 8.3 Hz), 8.60 (1H, s)

TABLE 41 Ex No. Strc ¹H-NMR δ ppm (DMSO-d6): 238

2.94 (3H, s), 3.20-3.50 (2H, m), 4.00-4.15 (2H, m), 6.90-7.40 (5H, m),7.65 (1H, d, J = 8.5 Hz), 8.00 (1H, d, J = 7.8 Hz), 8.53 (1H, s) 239

1.78 (3H, s), 1.80-1.95 (2H, m), 3.05-3.30 (2H, m), 3.95-4.15 (2H, m),6.95-7.35 (4H, m), 7.60-7.70 (1H, m), 7.80-8.10 (2H, m), 8.52 (1H, s)240

1.85-2.00 (2H, m), 2.29 (3H, s), 3.05-3.20 (2H, m), 4.07 (2H, t, J = 6.0Hz), 7.00-7.10 (2H, m), 7.15 (1H, dd, J = 1.9 Hz), 7.20-7.35 (2H, m),7.64 (1H, d, J = 8.8 Hz), 8.01 (1H, d, J = 9.1 Hz), 8.53 (1H, s) 241

5.43 (2H, s), 7.16 (1H, s), 7.25-7.55 (5H, m), 7.80-8.20 (4H, m), 8.71(1H, s), 8.88 (1H, s)

TABLE 42 Ref. No. Strc (Solv) ¹H-NMR δ ppm: 24

(CDCl3) 2.22 (3H, s), 3.91 (3H, s), 6.85-7.15 (3H, m) 25

(CDCl3) 2.33 (3H, s), 5.15 (1H, s), 7.06 (1H, d, J = 11.3 Hz), 7.49 (1H,d, J = 6.2 Hz) 26

(CDCl3) 2.28 (3H, s), 3.89 (3H, s), 7.00-7.10 (1H, m), 7.46 (1H, d, J =6.3 Hz) 27

(CDCl3) 2.30-2.40 (3H, m), 3.86 (3H, s), 3.95 (3H, s), 5.58 (1H, s),7.45 (1H, s), 7.69 (1H, s) 28

(CDCl3) 2.32 (3H, s), 3.93 (3H, s), 4.13 (2H, s), 7.40-7.45 (1H, m),7.66 (1H, s) 29

(DMSO-d6) 2.19 (3H, s), 3.78 (3H, s), 6.20- 6.30 (1H, m), 6.85 (1H, s),7.05-7.15 (1H, m), 7.24 (1H, s), 10.8 (1H, brs.) 30

(DMSO-d6) 2.20-2.30 (3H, m), 3.82 (3H, s), 6.98 (1H, s), 7.37 (1H, s),8.04 (1H, d, J = 2.8 Hz), 11.9 (1H, brs.) 31

(DMSO-d6) 2.98 (3H, s), 3.93 (3H, s), 7.15 (1H, d, J = 8.9 Hz),8.05-8.20 (2H, m) 32

(DMSO-d6) 2.22 (3H, s), 3.95 (3H, s), 4.30 (2H, s), 7.27 (1H, s), 8.09(1H, s) 33

(DMSO-d6) 2.22 (3H, s), 3.76 (3H, s), 6.20- 6.40 (1H, m), 6.90-7.25 (3H,m), 10.75 (1H, brs.)

TABLE 43 Ref. No. Strc (Solv) ¹H-NMR δ ppm: 34

(DMSO-d6) 2.24 (3H, s), 3.84 (3H, s), 7.03 (1H, s), 7.30 (1H, s), 8.06(1H, s), 11.92 (1H, brs.) 35

(CDCl3) 5.17 (2H, s), 6.35-6.55 (1H, m), 7.05- 7.65 (8H, m), 8.04 (1H,brs.) 36

(CDCl3) 5.24 (2H, s), 7.25-7.65 (6H, m), 7.70- 7.85 (1H, m), 7.90-8.05(1H, m), 8.59 (1H, brs.), 10.02 (1H, s) 37

(CDCl3) 5.21 (2H, s), 7.20-7.75 (8H, m), 8.5 (1H, brs.) 38

(CDCl3) 2.25-2.60 (3H, m), 5.10-5.45 (2H, m), 5.68 (1H, s), 7.20-7.70(6H, m), 7.80-8.10 (1H, m). 39

(CDCl3) 2.20-2.55 (3H, m), 6.35-6.55 (1H, m), 6.90-7.50 (3H, m), 8.04(1H, brs.). 40

(CDCl3) 2.30-2.50 (3H, m), 7.00-7.20 (1H, m), 7.70-7.90 (1H, m),8.05-8.25 (1H, m), 8.64 (1H, brs.), 10.02 (1H, s). 41

(CDCl3) 2.30-2.50 (3H, m), 7.00-7.20 (1H, m), 7.45-7.80 (2H, m), 8.51(1H, brs.). 42

(CDCl3) 3.94 (3H, s), 5.19 (2H, s), 6.35-6.50 (1H, m), 6.80-6.95 (1H,m), 7.00-7.20 (2H, m), 7.25-7.55 (5H, m), 7.92 (1H, brs.).

TABLE 44 Ref. No. Strc (Solv) ¹H-NMR δ ppm: 43

(CDCl3) 3.74 (3H, s), 5.02 (2H, s), 7.15-7.65 (6H, m), 7.79 (1H, s),8.25-8.50 (1H, m), 9.86 (1H, s). 44

(CDCl3) 3.84 (3H, s), 5.12 (2H, s), 7.00-7.20 (2H, m), 7.25-7.55 (5H,m), 7.90-8.15 (1H, m). 45

(DMSO-d6) 3.81 (3H, s), 6.30-6.45 (1H, m), 7.10-7.35 (3H, m), 10.96 (1H,brs.) 46

(DMSO-d6) 2.29 (3H, s), 2.35 (3H, s), 3.62 (3H, s), 6.20-6.40 (1H, m),6.90-7.30 (2H, m), 10.80 (1H, brs.) 47

(DMSO-d6) 3.85 (3H, s), 6.40-6.60 (1H, m), 7.25-7.70 (3H, m), 11.30 (1H,brs.) 48

(DMSO-d6) 2.95-3.05 (6H, m), 7.26 (1H, d, J = 9.5 Hz), 8.20-8.40 (2H, m)49

(DMSO-d6) 3.00-3.15 (6H, m), 4.36 (2H, s), 7.32 (1H, s), 8.39 (1H, s) 50

(DMSO-d6) 2.63 (6H, s), 6.40-6.60 (1H, m), 7.50-7.80 (3H, m), 11.39 (1H,brs) 51

(DMSO-d6) 1.25-1.45 (3H, m), 2.67 (6H, s), 4.20-4.45 (2H, m), 6.75-6.90(1H, m), 7.25- 8.25 (7H, m)

TABLE 45 Ref. No. Strc (Solv) ¹H-NMR δ ppm: 52

(DMSO-d6) 1.35 (3H, t, J = 7.1 Hz), 2.70 (6H, s), 4.37 (2H, q, J = 7.1Hz), 7.79 (1H, s), 7.85- 8.30 (4H, m), 8.36 (1H, s), 8.89 (1H, s), 10.09(1H, s) 53

(DMSO-d6) 2.24 (3H, s), 2.29 (3H, s), 6.15- 7.20 (3H, m), 7.40 (1H, s),10.58 (1H, brs)

TABLE 46 Ref. No. Strc 54

55

56

57

58

59

60

61

62

63

TABLE 47 Ex No. Strc (Solv) ¹H-NMR δ ppm: 242

(DMSO-d6) 1.36 (3H, t, J = 7.1 Hz), 2.27 (3H, s), 3.90 (3H, s), 4.36(2H, q, J = 7.1 Hz), 7.17 (1H, s), 7.52 (1H, s), 7.75-8.25 (4H, m), 8.55(1H, s) 243

(CDCl3) 1.44 (3H, t, J = 7.1 Hz), 4.44 (2H, d, J = 7.1 Hz), 5.25 (2H,s), 7.25-7.85 (10H, m), 8.15-8.35 (2H, m) 244

(CDCl3) 1.44 (3H, t, J = 7.1 Hz), 4.45 (2H, d, J = 7.1 Hz), 5.55 (1H,s), 7.43 (1H, s), 7.45-7.65 (3H, m), 7.80 (1H, s), 8.15-8.35 (2H, m) 245

(CDCl3) 1.44 (3H, t, J = 7.2 Hz), 4.01 (3H, s), 4.44 (2H, q, J = 7.2Hz), 7.20-7.35 (1H, m), 7.45-7.65 (3H, m), 7.79 (1H, s), 8.20-8.35 (2H,m) 246

(CDCl3) 1.45 (3H, t, J = 7.1 Hz), 4.46 (2H, d, J = 7.1 Hz), 7.45-7.65(2H, m), 7.67 (1H, s), 7.81 (1H, s), 7.93 (1H, s), 8.20-8.40 (2H, m) 247

(CDCl3) 1.44(3H, t, J = 7.1 Hz), 2.52 (3H, s), 4.45 (2H, q, J = 7.1 Hz),7.45-7.65 (3H, m), 7.68 (1H, s), 7.79 (1H, s), 8.20-8.35 (2H, m) 248

(CDCl3) 1.30-1.60 (3H, m), 2.42 (3H, s), 4.30- 4.55 (2H, m), 7.10-7.35(1H, m), 7.45-7.70 (3H, m), 7.78 (1H, s), 8.15-8.35 (2H, m).

TABLE 48 Ex No. Strc (Solv) ¹H-NMR δ ppm: 249

(CDCl3) 1.45 (3H, t, J = 7.2 Hz), 2.35-2.50 (3H, m), 4.46 (2H, q, J =7.2 Hz), 7.45-7.65 (2H, m), 8.00-8.15 (1H, m), 8.20 (1H, s), 8.40- 8.60(1H, m), 9.10-9.30 (1H, m). 250

(CDCl3) 1.42 (3H, t, J = 7.1 Hz), 2.35-2.45 (3H, m), 3.55 (3H, s), 4.41(2H, q, J = 7.1 Hz), 5.31 (2H, s), 7.05-7.40 (3H, m), 7.50-7.65 (1H, m),7.77 (1H, s), 7.90-8.05 (1H, m). 251

(CDCl3) 1.45 (3H, t, J = 7.1 Hz), 4.00 (3H, s), 4.45 (2H, q, J = 7.1Hz), 5.15 (2H, s), 6.98 (1H, s), 7.22 (1H, s), 7.25-7.50 (7H, m), 7.66(1H, s), 8.10-8.30 (2H, m). 252

(CDCl3)1.44 (3H, t, J = 7.2 Hz), 4.02 (3H, s), 4.44 (2H, q, J = 7.2 Hz),7.12 (1H, s), 7.19 (1H, s), 7.45-7.65 (2H, m), 7.68 (1H, s), 8.15-8.35(2H, m). 253

(CDCl3) 0.50-0.70 (2H, m), 0.85-1.05 (2H, m), 1.44 (3H, t, J = 7.2 Hz),2.10-2.34 (1H, m), 3.97 (3H, s), 4.44 (2H, q, J = 7.2 Hz), 7.03 (1H, s),7.17 (1H, s), 7.40-7.65 (2H, m), 7.71 (1H, s), 8.10-8.40 (2H, m). 254

(CDCl3) 1.44 (3H, t, J = 7.1 Hz), 2.36 (3H, s), 4.44 (2H, q, J = 7.1Hz), 7.17 (1H, s), 7.31 (1H, s), 7.45-7.65 (2H, m), 7.72 (1H, s),8.15-8.35 (2H, m).

TABLE 49 Ex No. Strc (Solv) ¹H-NMR δ ppm: 255

(CDCl3) 1.44 (3H, t, J = 7.1 Hz), 2.37 (3H, s), 2.41 (3H, s), 4.44 (2H,q, J = 7.1 Hz), 7.33 (1H, s), 7.45-7.65 (3H, m), 7.72 (1H, s), 8.15-8.35(2H, m). 256

(DMSO-d6) 1.36 (3H, t, J = 7.1 Hz), 3.96 (3H, s), 4.36 (2H, q, J = 7.1Hz), 7.35 (4H, m), 8.66 (1H, s) 257

(DMSO-d6) 7.10-8.20 (6H, m), 8.59 (1H, s), 10.05 (1H, s), 13.22 (1H,brs.) 258

(DMSO-d6) 3.20-3.40 (6H, m), 3.60-3.80 (4H, m), 4.20-4.60 (4H, m),7.35-8.25 (6H, m), 8.66 (1H, s).

TABLE 50 Ex No. Strc 259

260

261

262

263

264

265

266

267

268

269

270

TABLE 51 Ex No. Strc 271

272

273

274

275

276

277

278

279

280

281

282

TABLE 52 Ex No. Strc 283

TABLE 53 Ex No. Strc ¹H-NMR δ ppm: DMSO-d6 284

2.28 (3H, s), 3.82 (3H, s), 7.05-7.15 (1H, s), 7.45-7.55 (1H, s),7.75-7.90 (2H, m), 8.10- 8.25 (2H, m), 8.47 (1H, s), 13.19 (1H, brs.)285

2.27 (3H, s), 3.90 (3H, s), 7.10-8.25 (6H, m), 8.53 (1H, s) 286

7.25-7.35 (1H, m), 7.40-7.60 (7H, m), 7.80- 7.90 (2H, m), 8.10-8.25 (2H,m), 8.75 (1H, s), 13.3 (1H, brs.) 287

3.96 (3H, s), 7.35-8.20 (6H, m), 8.64 (1H, s), 13.26 (1H, brs.) 288

2.33 (3H, s), 2.62 (3H, s), 3.69 (3H, s), 7.35 (1H, s), 7.65-8.20 (4H,m), 8.58 (1H, s), 13.28 (1H, brs.) 289

2.56 (3H, s), 3.84 (3H, s), 7.14 (1H, d, J = 9.2 Hz), 7.45-7.55 (1H, m),7.75-7.85 (2H, m), 8.10-8.20 (2H, m), 8.65 (1H, s), 13.24 (1H, brs.) 290

0.55-0.75 (2H, m), 0.80-1.00 (2H, m), 2.05- 2.30 (1H, m), 3.93 (3H, s),7.09 (1H, s), 7.18 (1H, s), 7.64 (2H, m), 8.05-8.25 (2H, m), 8.52 (1H,s), 13.18 (1H, brs.).

TABLE 54 Ex No. Strc ¹H-NMR δ ppm: DMSO-d6 291

2.33 (3H, s), 2.62 (3H, s), 3.36 (3H, s), 3.60- 3.95 (4H, m), 7.74 (1H,s), 7.76-8.25 (4H, m), 8.57 (1H, s) 292

2.27 (3H, s), 2.56 (3H, s), 6.50-8.50 (7H, m) 293

3.97 (3H, s), 7.40 (1H, s), 7.65-7.95 (3H, m), 8.05-8.25 (2H, m), 8.68(1H, s), 13.22 (1H, brs.) 294

3.20-3.45 (3H, m), 3.60-3.90, (2H, m), 4.15- 4.45 (2H, m), 4.23 (1H, s),7.65-7.95 (3H, m), 8.05-8.30 (2H, m), 8.68 (1H, s), 13.23 (1H, brs.) 295

2.35-2.60 (3H, m), 7.65-7.95 (4H, m), 8.05- 8.25 (2H, m), 8.70 (1H, s),13.24 (1H, brs.) 296

2.24 (3H, s), 7.03 (1H, s), 7.44 (1H, s), 7.60- 7.90 (2H, m), 7.95-8.30(2H, m), 8.46 (1H, s), 9.56 (1H, brs.), 13.20 (1H, brs.). 297

2.34 (3H, s), 2.37 (3H, s), 7.40-7.60 (2H, m), 7.70-7.85 (2H, m),8.05-8.25 (2H, m), 8.53 (1H, s).

TABLE 55 Ex No. Strc ¹H-NMR δ ppm: DMSO-d6 298

2.38 (3H, s), 7.30-8.40 (6H, m), 8.66 (1H, s), 13.22 (1H, brs.) 299

7.10-7.65 (3H, m), 7.70-7.90 (3H, m), 8.10- 8.25 (2H, m), 8.79 (1H, s),13.29 (1H, brs.) 300

2.72 (6H, s), 7.75-7.90 (3H, m), 7.98 (1H, s), 8.10-8.25 (2H, m), 8.87(1H, s) 301

1.32 (6H, d, J = 6.0 Hz), 4.80-5.10 (1H, m), 7.55 (1H, s), 7.70-8.30(5H, m), 8.83 (1H, s), 13.33 (1H, brs.) 302

1.40 (3H, t, J = 7.1 Hz), 4.21 (2H, q, J = 7.1 Hz), 7.30-8.25 (6H, m),8.65 (1H, s), 13.25 (1H, brs.) 303

1.32 (6H, d, J = 6.1 Hz), 4.60-4.90 (1H, m), 7.30-8.30 (6H, m), 8.66(1H, s), 13.27 (1H, brs.) 304

0.96 (6H, d, J = 6.7 Hz), 1.50-2.00 (3H, m), 4.10-4.30 (2H, m),7.30-8.30 (6H, m), 8.65 (1H, s), 13.29 (1H, brs.)

TABLE 56 Ex No. Strc ¹H-NMR δ ppm: DMSO-d6 305

3.33 (3H, s), 3.65-3.80 (2H, m), 4.20-4.40 (2H, m), 7.35-8.25 (6H, m),8.66 (1H, s), 13.29 (1H, brs.) 306

3.89 (3H, s), 7.14(1H, s), 7.80-8.15 (2H, m), 8.35-8.55 (1H, m), 8.79(1H, s), 8.95-9.15 (1H, m), 9.37 (1H, brs.), 13.48 (1H, brs.). 307

2.39 (3H, s), 7.55-7.80 (1H, m), 7.90-8.10 (1H, m), 8.30-8.60 (2H, m),8.90-9.25 (2H, m), 13.52 (1H, brs.). 308

3.44 (3H, s), 5.38 (2H, s), 7.26-7.55 (4H, m), 7.65-8.00 (3H, m), 8.68(1H, s), 12.99 (1H, brs.). 309

7.20-7.30 (2H, m), 7.35-7.50 (2H. m), 7.67 (1H, dd, J = 8.0 Hz, 1.0 Hz),8.01 (1H, d, J = 8.7 Hz), 8.81 (1H, s) 310

2.72 (3H, s), 7.14 (1H, d, J = 7.2 Hz), 7.20-7.35 (3H, m), 7.52 (1H, d,J = 8.5 Hz), 8.00 (1H, d, J = 8.1 Hz), 8.66 (1H, s) 311

3.95 (3H, s), 7.15-8.05 (5H, m), 8.63 (1H, s)

TABLE 57 Ex No. Strc ¹H-NMR δ ppm: DMSO-d6 312

7.10-7.30 (3H, m), 7.50-8.05 (2H, m), 8.57 (1H, s), 10.06 (1H, s) 313

2.55 (3H, s), 3.84 (3H, s), 7.14 (1H, d, J = 9.0 Hz), 7.18-7.30 (2H, m),7.45-7.55 (1H, m), 7.95-8.05 (1H, m), 8.63 (1H, s), 314

2.27 (3H, s), 3.90 (3H, s), 7.10-7.25 (3H, m), 7.52 (1H, s), 7.90-8.05(1H, m), 8.50 (1H, s) 315

7.20-7.40 (2H, m), 7.65-7.80 (1H, m), 7.85- 7.95 (1H, m), 8.03 (1H, d, J= 8.6 Hz), 8.05-8.20 (1H, m), 8.88 (1H, s) 316

2.38 (3H, s), 7.10-7.35 (2H, m), 7.40-7.75 (2H, m), 7.90-8.20 (1H, m),8.64 (1H, s). 317

3.87 (3H, s), 6.95-7.35 (4H, m), 7.90-8.10 (1H, m), 8.39 (1H, s), 9.38(1H, brs.). 318

7.10-7.45 (4H, m), 7.59 (1H, d, J = 7.8 Hz), 7.95 (1H, d, J = 8.2 Hz),8.63 (1H, s)

TABLE 58 Ex No. Strc ¹H-NMR δ ppm: DMSO-d6 319

4.00 (3H, s), 7.10-8.10 (5H, m), 8.81 (1H, s) 320

7.10-7.65 (5H, m), 7.77 (1H, d, J = 9.0 Hz), 8.01 (1H, d, J = 8.4 Hz),8.76 (1H, s), 321

7.15-7.30 (1H, m), 7.35-7.50 (3H, m), 7.70- 7.85 (2H, m), 8.60-8.65 (1H,m) 322

2.45 (3H, s), 7.20-7.30 (3H, m), 7.52 (1H, s), 7.64 (1H, d, J = 8.0 Hz),8.01 (1H, d, J = 8.0 Hz), 8.57 (1H, s) 323

1.32 (3H, t, J = 7.3 Hz), 2.24 (3H, s), 3.44 (3H, s), 4.31 (2H, q, J =7.3 Hz), 5.38 (2H, s), 7.03 (1H, s), 7.30-7.50 (3H, m), 7.86 (1H, d, J =8.4 Hz), 8.44 (1H, s), 9.56 (1H, s) 324

2.28 (3H, s), 3.70-3.80 (2H, m), 4.15-4.30 (2H, m), 7.10-7.30 (3H, m),7.53 (1H, s), 7.95- 8.05 (1H, m), 8.50 (1H, s) 325

2.24 (3H, s) 7.02 (1H, s), 7.15-7.25 (2H, m), 7.46 (1H, s), 7.98 (1H, d,J = 9.0 Hz), 8.44 (1H, s), 9.56 (1H, s)

TABLE 59 Ex No. Strc ¹H-NMR δ ppm: DMSO-d6 326

1.32 (6H, d, J = 5.9 Hz), 2.25 (3H, s), 4.65-4.80 (1H, m), 7.10-8.10(5H, m), 8.49 (1H, s) 327

1.25 (3H, t, J = 7.5 Hz), 2.78 (2H, q, J = 7.5 Hz), 7.10-7.40 (3H, m),7.50-7.75 (2H, m), 7.90-8.10 (1H, m), 8.63 (1H, s) 328

2.38 (3H, s), 6.70-6.80 (1H, m), 7.01 (1H, d, J = 2.3 Hz), 7.49 (1H, d,J = 10.6 Hz), 7.60-7.80 (1H, m), 7.89 (1H, d, J = 8.5 Hz), 8.58 (1H, s)

TEST EXAMPLE 1 Xanthine Oxidase Inhibitory Activity

(1) Preparation of Test Compounds

Test compounds were dissolved in DMSO (Wako) at 40 mM concentration andthen diluted to intended concentrations with phosphate-buffered saline(PBS).

(2) Method for Measurement

Xanthine oxidase (from bovine milk, Sigma) was prepared withphosphate-buffered saline (PBS) at 0.02 units/mL, and then the solutionwas added to 96 well plates at 50 μL/well. In addition, test compoundsdiluted with PBS were added at 50 μL/well. Xanthine (Wako) at 200 μMprepared with PBS was added at 100 μL/well, and the reaction wasconducted for 10 minutes at room temperature. Absorbance at 290 nm wasmeasured using a microplate reader SpectraMax Plus 384 (Moleculardevice). The absorbance under a condition without xanthine is 0%, andcontrol without test compounds is 100%. Fifty % inhibitory concentrationof a test compound (IC₅₀) was calculated (Table 60). Ex. No in the tableindicates Example number.

TABLE 60 Ex. No IC₅₀ (nM) 3 6.5 5 33.6 8 41.5 9 12.5 12 7.0 15 15.5 1712.1 19 96.0 27 14.6 29 43.3 32 91.1 34 48.3 42 175.3 45 72.9 47 58.6143 24.4 149 38.0 150 20.6 151 22.4 152 15.8 153 12.2 154 19.0 155 111.7156 11.9 157 14.1 158 9.5 159 14.4 160 11.3 161 49.8 162 16.5 165 111.2166 7.2 167 10.9 170 20.0 171 10.9 172 8.0 174 24.4 175 22.2 176 18.3177 16.4 178 12.9 179 8.0 180 29.0 181 17.2 182 16.3 183 7.5 184 138.3185 40.2 186 49.7 187 16.4 188 5.0 189 13.9 190 5.4 191 3.9 192 4.3 1934.6 194 8.3 195 14.5 196 6.7 197 9.0 198 54.6 199 49.2 200 39.4 201 5.5202 61.8 203 7.1 205 27.6 206 7.2 207 7.3 208 6.0 209 11.0 210 7.0 2116.2 212 5.1 213 7.2 214 11.0 215 10.5 216 7.4 217 6.0 218 6.0 219 8.3220 9.4 221 71.5 222 41.8 223 7.5 224 9.7 225 4.6 226 10.0 227 10.4 2287.5 229 7.1 230 67.1 231 29.1 232 42.5 233 7.2 234 86.5 235 14.2 23712.6 238 8.3 239 6.5 240 9.8 286 58 287 16 288 10 293 14 295 9 298 12300 96 303 10 307 13 308 45 316 10 318 12

TEST EXAMPLE 2 Inhibitory Activity of Uric Acid Transport withBrush-Border Membrane Vesicles (BBMV)

Inhibitory activity of uric acid transport of test compounds wasperformed on the basis of methods described in a reference (Am. J.Physiol. 266 (Renal Fluid Electrolyte Physiol. 35): F797-F805, 1994)with a partial modification.

(1) Preparation of BBMV from Human Kidney Cortex

BBMV from human kidney cortex were purchased from KAC. Renal cortex wasdissected from human kidney and cut into small pieces. Then, the cortexwas homogenized in 5 volumes of ice-cold isotonic buffer (300 mMmannitol, 5 mM ethyleneglycol-bis-(β-aminoethylether)-N,N,N′,N′-tetraacetic acid (EGTA), 12 mMtris(hydroxymethyl)aminomethane (Tris).HCl, pH 7.4). After adding 1 Mmagnesium chloride to a final concentration of 12 mM, and then thesuspension was mixed and allowed to stand on ice for 15 minutes. Thehomogenized solution was centrifuged at 2,500×g for 15 minutes at 4° C.,furthermore, the supernatant was centrifuged at 30,000×g for 30 minutesat 4° C. The pellet was resuspended in ice-cold buffer 1 (150 mMmannitol, 2.5 mM EGTA, 6 mM Tris.HCl, pH 7.4). After adding 1 Mmagnesium chloride to a final concentration of 12 mM, and then thesuspension was mixed and allowed to stand on ice for 15 minutes. Aftercentrifugation again at 2,500×g for 15 minutes at 4° C., furthermore,the supernatant was centrifuged at 30,000×g for 30 minutes at 4° C. Thepellet was resuspended in ice-cold buffer 2 (100 mM mannitol, 100 mMpotassium gluconate, 20 mM2-[4-(2-hydroxyethyl)-1-piperazinyl]ethanesulfonic acid (Hepes)-Tris, pH7.4). After centrifugation at 30,000×g for 30 minutes at 4° C., thepellet was resuspended in buffer 2, and then the protein concentrationwas determined.

(2) Preparation of Test Compounds

Test compounds were dissolved in DMSO (Wako) at 40 mM concentration andthen diluted to 2 times higher concentration than intended with Cl⁻gradient buffer (100 mM mannitol, 100 mM potassium gluconate, 20 mMHepes-Tris, pH 7.4). Cl⁻ gradient buffer without test compounds was usedfor control. Furthermore, an equal volume of CF gradient buffercontaining ¹⁴C-labeled uric acid (Moravek) and probenecid (Wako) wasadded to test compounds and control, and finally assay buffer including40 μM uric acid and 5 μM probenecid was prepared. To measure the uptakeof ¹⁴C-labeled uric acid through gradient independent manner, assaybuffer was prepared with CF equilibrium buffer (100 mM mannitol, 60 mMpotassium gluconate, 40 mM potassium chloride, 20 mM Hepes-Tris, pH 7.4)in place of Cl⁻ gradient buffer.

(3) Method for Measurement

BBMV were thawed on ice. After adding 8 mL of intravesicular buffer (100mM mannitol, 60 mM potassium gluconate, 40 mM potassium chloride, 20 mMHepes-Tris, pH 7.4) to 200 μL of prepared BBMV (protein concentration:16 mg/mL), the BBMV were suspended through 25-gauge needle and allowedto equilibrate at room temperature for 60 minutes. After centrifugationat 30,000×g for 30 minutes at 4° C., the pellet was resuspended in 1.2mL of intravesicular buffer. The suspension was kept on ice until thebeginning of the measurement. The uptake of uric acid into BBMV wasmeasured by the rapid-filtration technique. Requirement of BBMV (20 μL/1reaction) was warmed for 20 minutes at room temperature. The uptake ofuric acid was initiated by mixing with 100 μL of assay buffer. Afterincubation for 20 seconds at room temperature, 3 mL of ice-cold stopsolution (300 mM mannitol, 60 mM sodium sulfate, 100 μM probenecid(Wako), 5 mM Tris-H₂SO₄, pH 7.4) was added, and then the solutions werefiltered rapidly through nitrocellulose filters (0.65 μm pore size,Sartorius) kept under suction. Furthermore, filters were washed twicewith 3 mL of stop solution and dissolved in 10 mL of Filter-Count(PerkinElmer), and the radioactivity was counted in a liquidscintillation counter (PerkinElmer). The radioactivity associated withthe filters in the absence of BBMV was used as corrections. In addition,percent inhibition of test compounds at 10 μM was calculated accordingto the formula described below (Table 61). Ex. No, Conc. and inhibition% in the table indicate Example number, concentration of test compounds(μM) and percent inhibition (%), respectively.

Percent inhibition (%)=[1−(B−C)/(A−C)]×100

-   A: Radioactivity in control-   B: Radioactivity in the case of addition of test compounds-   C: Radioactivity in Cl⁻ equilibrium buffer

TABLE 61 Ex. No Conc. (μM) inhibition % 237 10 64

TEST EXAMPLE 3 Inhibitory Activity of Uric Acid Transport with HumanURAT1 Expressing Cells

(1) Preparation of Transiently Human URAT1 Expressing Cells

Full length human URAT1 cDNA (NCBI Accession No. NM_(—)144585) wassubcloned into expression vector, pcDNA3.1 (Invitrogen). Human URAT1expression vector was transfected into COS7 cells (RIKEN CELL BANKRCB0539) using Lipofectamine 2000. COS7 cells were cultured incollagen-coated 24 well plates (Asahi Techno Glass) at 2×10⁵/well inD-MEM culture medium (Invitrogen) containing 10% fetal bovine serum(Sanko Junyaku) for 2 hours at 37° C. under the condition of 5% CO₂. For1 well, 2 μL of Lipofectamine 2000 was diluted in 50 μL of OPTI-MEM(Invitrogen) and allowed to stand at room temperature for 7 minutes(hereinafter referred to as Lipo2000-OPTI). For 1 well, 0.8 μg of humanURAT1 expression vector was diluted in 50 μL of OPTI-MEM (Invitrogen)and combined gently with Lipo2000-OPTI. After standing at roomtemperature for 25 minutes, the mixture was added to COS7 cells at 100μL/well. Furthermore, COS7 cells were cultured for 2 days at 37° C.under the condition of 5% CO₂ and used for measuring inhibitory activityon the uptake.

(2) Preparation of Test Compounds

Test compounds were dissolved in DMSO (Wako) at 10 mM concentration andthen diluted to 2 times higher concentration than intended withpre-treatment buffer (125 mM sodium gluconate, 4.8 mM potassiumgluconate, 1.2 mM potassium dihydrogen phosphate, 1.2 mM magnesiumsulfate, 1.3 mM calcium gluconate, 5.6 mM glucose, 25 mM Hepes, pH 7.4).Pre-treatment buffer without test compounds was used for control. Inaddition, an equal volume of pre-treatment buffer containing ¹⁴C-labeleduric acid (Moravek) was added to test compounds and control, and finallyassay buffer including 20 μM uric acid was prepared.

(3) Method for Measurement

All tests were performed on hot-plate at 37° C. Pre-treatment buffer andassay buffer were incubated at 37° C. and then used for assays. Mediumwas removed from plates, and 700 μL of pre-treatment buffer was added,and the cells were pre-incubated for 10 minutes. After repeating samestep, pre-treatment buffer was removed, and assay buffer was added at400 μL/well. The uptake reaction was carried out for 5 minutes. Afterterminating the reaction, assay buffer was rapidly removed, and thecells were washed twice with addition of ice-cold pre-treatment bufferat 1.2 mL/well. Then, the cells were lysed by addition of 0.2 N sodiumhydroxide at 300 μL/well. The lysed solutions were transferred intoPicoplate (PerkinElmer), and Microscinti 40 (PerkinElmer) was added at600 μL/well. After mixing, the radioactivity was counted in a liquidscintillation counter (PerkinElmer). The radioactivity in COST cells nottransfected with URAT1 expression vector was also counted under the samecondition as control. In addition, percent inhibition of test compoundsat 10 μM was calculated according to the formula described below (Table62). In the table Ex. No, Conc. and inhibition % indicate Examplenumber, concentration of test compound (μM) and percent inhibition (%),respectively.

Percent inhibition (%)=[1−(B−C)/(A−C)]×100

-   A: Radioactivity in control-   B: Radioactivity in the case of addition of test compounds-   C: Radioactivity in COST cells not transfected with URAT1 expression    vector

TABLE 62 Ex. No Conc. (μM) inhibition % 193 10 47 194 10 64

TEST EXAMPLE 4

Serum Hypouricemic Effect

(1) Method for Measurement

Test compounds at 3 mg/kg suspended in 0.5% methylcellulose solutionwere administered orally to overnight fasted male CD (SD) IGS rats(5-week-old, Charls River Japan). At 2 hours after administration, bloodwas collected under ether anesthesia from abdominal aorta, and serum wasseparated according to general method. Serum uric acid values weredetermined by use of uric acid measurement kit (Uric acid C-Test Wako:Wako), and percent decrease in uric acid was calculated according to theformula described below.

Percent decrease in uric acid (%)=(Serum uric acid values in controlanimals—Serum uric acid values in animals administered testcompounds)×100/Serum uric acid values in control animals

(2) Results

Compounds of example 3, 188, 191 and 192 have over 60% hypouricemiceffect at 2 hours after oral administration. As results described above,it is confirmed that compounds in the present invention have a potenteffect reducing serum uric acid.

Industrial Applicability

The (aza)indole derivatives represented by the above general formula (I)of the present invention or prodrugs, or pharmaceutically acceptablesalts thereof exert an excellent xanthine oxidase inhibitory activity,and therefore, can exert an inhibitory activity of uric acid productionand lower the blood uric acid level. Therefore, the present inventioncan provide an agent for the prevention or treatment of hyperuricemia,gouty tophus, gouty arthritis, renal disorder associated withhyperuricemia, urinary calculi or the like.

The invention claimed is:
 1. A method of lowering serum uric acid level,the method comprising administering a pharmaceutically effective amountof a compound represented by the general formula (IA):

wherein R¹ represents a halogen atom, cyano, perfluoro(lower alkyl),-A^(A), -A-D-E-G or —N(-D-E-G)₂, with the proviso that two (-D-E-G) areoptionally different from each other; in the formula, A^(A) represents ahydrogen atom, hydroxy, thiol, —CHO, carboxy, —CONHR³, —NHR³, —N(R³)CHO,—N(R³)CONHR⁴ or —SO₂NHR³; A represents a single bond, —O—, —S—, —CO—,—COO—, —CON(R³)—, —SO₂—, —SO₂N(R³)—, —N(R³)—, —N(R³)CO—, —N(R³)COO—,—N(R³)SO₂— or —N(R³)CONR⁴—, wherein R³ and R⁴ independently represent ahydrogen atom or lower alkyl; D represents an optionally substitutedlower alkylene, an optionally substituted lower alkenylene, anoptionally substituted lower alkynylene, an optionally substitutedcycloalkylene, an optionally substituted heterocycloalkylnene, anoptionally substituted arylene or an optionally substitutedheteroarylene, with the proviso that D is optionally further substitutedby -E-G; E represents a single bond, —O—, —N(R⁵)—, —S—, —CO—, —COO—,—CON(R⁵)—, —SO₂—, —SO₂N(R⁵)—, —N(R⁵)CO—, —N(R⁵)COO—, —N(R⁵)SO₂— or—N(R⁵)CON(R⁶)— with the proviso that R⁵ and R⁶ independently represent ahydrogen atom or lower alkyl; and G represents a hydrogen atom, anoptionally substituted lower alkyl, an optionally substituted loweralkenyl, an optionally substituted lower alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted heterocycloalkyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted cycloalkyl(lower alkyl), an optionallysubstituted heterocycloalkyl(lower alkyl), an optionally substitutedaryl(lower alkyl) or an optionally substituted heteroaryl(lower alkyl)with the proviso that when G is a hydrogen atom, E is a single bond,—O—, —N(R⁵)—, —S—, —COO—, —CON(R⁵)—, —N(R⁵)CO—, —N(R⁵)CON(R⁶)— or—SO₂N(R⁵)—, or R⁵ and R⁶ optionally bind together to form a ring, or aprodrug thereof, or a pharmaceutically acceptable salt thereof, to apatient in need of serum uric acid lowering.
 2. A method as claimed inclaim 1, wherein the compound is selected from the group consisting of:4-(3-cyano-indol-1-yl)-2-hydroxy-benzoic acid,4-(3-cyano-5-methyl-indol-1-yl)-2-hydroxy-benzoic acid,4-(3-cyano-6-chloro-indol-1-yl)-2-hydroxy-benzoic acid,4-(3-cyano-5-fluoro-indol-1-yl)-2-hydroxy-benzoic acid,4-(3-cyano-6-fluoro-indol-1-yl)-2-hydroxy-benzoic acid,4-(3-cyano-6-trifluoromethyl-indol-1-yl)-2-hydroxy-benzoic acid,4-(3-cyano-5-methoxy-indol-1-yl)-2-hydroxy-benzoic acid,4-(5-chloro-3-cyano-indol-1-yl)-2-hydroxy-benzoic acid,4-(3-cyano-5-hydroxy-indol-1-yl)-2I -hydroxy-benzoic acid,4-(3-cyano-4-hydroxy-indol-1-yl)-2-hydroxy-benzoic acid,4-(3-cyano-6-hydroxy-indol-1-yl)-2-hydroxy-benzoic acid,4-(3-cyano-6-methoxy-indol-1-yl)-2-hydroxy-benzoic acid,4-(3-cyano-4-fluoro-indol-1-yl)-2-hydroxy-benzoic acid, and4-(3-cyano-6-isopropyl-indol-1-yl)-2-hydroxy-benzoic acid, or apharmaceutically acceptable salt thereof.
 3. A method as claimed inclaim 1, wherein the compound is selected from the group consisting of:4-(3-cyano-indol-1-yl)-2-hydroxy-benzoic acid,4-(3-cyano-5-fluoro-indol-1-yl)-2-hydroxy-benzoic acid,4-(3-cyano-6-fluoro-indol-1-yl)-2-hydroxy-benzoic acid, and4-(3-cyano-5-hydroxy-indol-1-yl)-2-hydroxy-benzoic acid, or apharmaceutically acceptable salt thereof.
 4. A method of treating adisorder selected from the group consisting of hyperuricemia, goutytophus, gouty arthritis, renal disorder associated with hyperuricemiaand urinary calculi, the method comprising administering apharmaceutically effective amount of a compound represented by thegeneral formula (IA):

wherein R^(l) represents a halogen atom, cyano, perfluoro(lower alkyl),-A^(A), -A-D-E-G or —N(-D-E-G)₂, with the proviso that two (-D-E-G) areoptionally different from each other; in the formula, A^(A) represents ahydrogen atom, hydroxy, thiol, —CHO, carboxy, —CONHR³, —NHR³, —N(R³)CHO,—N(R³)CONHR⁴ or —SO₂NHR³; A represents a single bond, —O—, —S—, —CO—,—COO—, —CON(R³)—, —SO₂—, —SO₂N(R³)—, —N(R³)—, —N(R³)CO—, —N(R³)COO—,—N(R³)SO₂— or —N(R³)CONR⁴— wherein R³ and R⁴ independently represent ahydrogen atom or lower alkyl; D represents an optionally substitutedlower alkylene, an optionally substituted lower alkenylene, anoptionally substituted lower alkynylene, an optionally substitutedcycloalkylene, an optionally substituted heterocycloalkylnene, anoptionally substituted arylene or an optionally substitutedheteroarylene with the proviso that D is optionally further substitutedby -E-G; E represents a single bond, —O—, —N(R⁵)—, —S—, —CO—, —COO—,—CON(R⁵)—, —SO₂—, —SO₂N(R⁵)—, —N(R⁵)CO—, —N(R⁵)COO—, —N(R⁵)SO₂— or—N(R⁵)CON(R⁶)— with the proviso that R⁵ and R⁶ independently represent ahydrogen atom or lower alkyl; and G represents a hydrogen atom, anoptionally substituted lower alkyl, an optionally substituted loweralkenyl, an optionally substituted lower alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted heterocycloalkyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted cycloalkyl(lower alkyl), an optionallysubstituted heterocycloalkyl(lower alkyl), an optionally substitutedaryl(lower alkyl) or an optionally substituted heteroaryl(lower alkyl),with the proviso that when G is a hydrogen atom, E is a single bond,—O—, —N(R⁵)—, —S—, —COO—, —CON(R⁵)—, —N(R⁵)CO—, —N(R⁵)CON(R⁶)— or—SO₂N(R⁵)—, or R⁵ and R⁶ optionally bind together to form a ring, or aprodrug thereof, or a pharmaceutically acceptable salt thereof, to apatient in need of treatment thereof.
 5. A method as claimed in claim 4,wherein the compound is selected from the group consisting of:4-(3-cyano-indol-1-yl)-2-hydroxy-benzoic acid,4-(3-cyano-5-methyl-indol-1-yl)-2-hydroxy-benzoic acid,4-(3-cyano-6-chloro-indol-1-yl)-2-hydroxy-benzoic acid,4-(3-cyano-5-fluoro-indol-1-yl)-2-hydroxy-benzoic acid,4-(3-cyano-6-fluoro-indol-1-yl)-2-hydroxy-benzoic acid,4-(3-cyano-6-trifluoromethyl-indol-1-yl)-2-hydroxy-benzoic acid,4-(3-cyano-5-methoxy-indol-1-yl)-2-hydroxy-benzoic acid,4-(5-chloro-3-cyano-indol-1-yl)-2-hydroxy-benzoic acid,4-(3-cyano-5-hydroxy-indol-1-yl)-2-hydroxy-benzoic acid,4-(3-cyano-4-hydroxy-indol-1-yl)-2-hydroxy-benzoic acid,4-(3-cyano-6-hydroxy-indol-1-yl)-2-hydroxy-benzoic acid,4-(3-cyano-6-methoxy-indol-1-yl)-2-hydroxy-benzoic acid,4-(3-cyano-4-fluoro-indol-1-yl)-2-hydroxy-benzoic acid, and4-(3-cyano-6-isopropyl-indol-1-yl)-2-hydroxy-benzoic acid, or apharmaceutically acceptable salt thereof.
 6. A method as claimed inclaim 4, wherein the compound is selected from the group consisting of:4-(3-cyano-indol-1-yl)-2-hydroxy-benzoic acid,4-(3-cyano-5-fluoro-indol-1-yl)-2-hydroxy-benzoic acid,4-(3-cyano-6-fluoro-indol-1-yl)-2-hydroxy-benzoic acid, and4-(3-cyano-5-hydroxy-indol-1-yl)-2-hydroxy-benzoic acid, or apharmaceutically acceptable salt thereof.
 7. A method as claimed inclaim 4, wherein the disorder is hyperuricemia.
 8. A method as claimedin claim 4, wherein the disorder is gouty tophus.
 9. A method as claimedin claim 4, wherein the disorder is gouty arthritis.
 10. A method asclaimed in claim 4, wherein the disorder is renal disorder associatedwith hyperuricemia.
 11. A method as claimed in claim 4, wherein thedisorder is urinary calculi.